Novel Antiretroviral Structures from Marine Organisms

molecules

Review Novel Antiretroviral Structures from Marine Organisms

Karlo Wittine , Lara Saftić,Željka Peršurić and Sandra KraljevićPavelić*

University of Rijeka, Department of Biotechnology, Centre for high-throughput technologies, Radmile Matejˇci´c2, 51000 Rijeka, Croatia * Correspondence: [email protected]; Tel.: +385-51-584-550

Academic Editor: Kyoko Nakagawa-Goto Received: 2 September 2019; Accepted: 19 September 2019; Published: 26 September 2019

Abstract: In spite of significant advancements and success in antiretroviral therapies directed against HIV infection, there is no cure for HIV, which scan persist in a human body in its latent form and become reactivated under favorable conditions. Therefore, novel antiretroviral drugs with different modes of actions are still a major focus for researchers. In particular, novel lead structures are being sought from natural sources. So far, a number of compounds from marine organisms have been identified as promising therapeutics for HIV infection. Therefore, in this paper, we provide an overview of marine natural products that were first identified in the period between 2013 and 2018 that could be potentially used, or further optimized, as novel antiretroviral agents. This pipeline includes the systematization of antiretroviral activities for several categories of marine structures including chitosan and its derivatives, sulfated polysaccharides, lectins, bromotyrosine derivatives, peptides, alkaloids, diterpenes, phlorotannins, and xanthones as well as adjuvants to the HAART therapy such as fish oil. We critically discuss the structures and activities of the most promising new marine anti-HIV compounds.

Keywords: antiretroviral agents; anti-HIV; marine metabolites; natural products; drug development

1. Introduction Human immunodeﬁciency virus (HIV) infections pose a global challenge given that in 2017, according to the World Health Organization data, 36.9 million people were living with HIV and additional 1.8 million people were becoming newly infected globally (Table1) . HIV targets immune cells and impairs the human defense against pneumonia, tuberculosis, and shingles as well as certain types of cancer [1]. The most advanced stage of HIV infection is the Acquired Immunodeﬁciency Syndrome (AIDS), which can take from two to 15 years to develop, depending on the individual [2].

Molecules 2019, 24, 3486; doi:10.3390/molecules24193486 www.mdpi.com/journal/molecules Molecules 2019, 24, 3486 2 of 36

Table 1. Summary of the global human immunodeﬁciency virus (HIV) epidemic (2017) according to Molecules 2019, 24, x FOR PEER REVIEW 2 of 40 World Health Organization (WHO) data.

Table 1. Summary of Peoplethe global Living human with immunodeficiency HIV People virus Newly (HIV) Infected epidemic (2017)HIV-Related according Deathsto World Health Organization (WHO)in 2017 data. with HIV in 2017 in 2017 People Living36.9 with million HIV People Newly1.8 Infected million with HIV-Related940,000 Deaths in total (31.3–43.9in 2017 million) HIV(1.4–2.4 in 2017 million) (670,000–1.32017 million) 36.9 million35 million 1.8 million1.6 million 940,000830 000 totaladults (31.3–43.9(29.6–41.7 million) million) (1.4–2.4(1.3–2.1 million) million) (670,000–1.3(590,000–1.2 million) million) 35 million18.2 million 1.6 million 830 000 adultswomen (29.6–41.7(15.6–21.4 million) million) (1.3–2.1 million) (590,000–1.2 million) 18.2 million16.8 million womenmen (15.6–21.4(13.9–20.4 million) million) 16.8 million1.8 million 180,000 110,000 childrenmen (< 15 years) (13.9–20.4(1.3–2.4 million) million) (110,000–260,000) (63,000–160,000) children (<15 1.8 million 180,000 110,000 years) (1.3–2.4 million) (110,000–260,000) (63,000–160,000) HIV has two viral forms: HIV-1 (the most common form that accounts for around 95% of all infectionsHIV worldwide) has two viral and forms: HIV-2 HIV-1 (relatively (the most uncommon common and form less that infectious). accounts for HIV-1 around consists 95% of of all groups M, N,infections O, andP worldwide) with at least and nine HIV-2 genetically (relatively distinctuncommon subtypes and less of infectious). HIV-1 within HIV-1 group consists M of (A, groups B, C, D, F, G, H,M, J, andN, O, K). and Additionally, P with at least di ninefferent genetically subtypes distin canct combinesubtypes geneticof HIV-1 material within group to form M (A, a hybridB, C, D, virus F, G, H, J, and K). Additionally, different subtypes can combine genetic material to form a hybrid known as the ‘circulating recombinant form’ (CRFs) (Figure1). HIV-2 consists of eight known groups virus known as the ‘circulating recombinant form’ (CRFs) (Figure 1). HIV-2 consists of eight known (A to H). Of these, only groups A and B are pandemic. The HIV-2 mechanism is not clearly defined groups (A to H). Of these, only groups A and B are pandemic. The HIV-2 mechanism is not clearly and neitherdefined isand its neither difference is its from difference HIV-1. from However, HIV-1. Ho thewever, transmission the transmission rate is much rate is lower much inlower HIV-2 in than in HIV-1.HIV-2 HIV-2 than in is HIV-1. estimated HIV-2 to is be estimated more than to be 55% more genetically than 55% genetically distinct from distinct HIV-1. from HIV-1.

F Group M G Group N H

HIV-1 Group O J Group P K Group A CRFs Group B

Group C

Group D

HIV-2 Group E

Group F

Group G

Group H

FigureFigure 1. 1.HIV HIV typestypes and strains strains classification. classiﬁcation.

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The HIV-1 genome has reading frames coding for structural and regulatory proteins. The gag gene encodes the Pr55Gag precursor of inner structural proteins p24 (capsid protein, CA), p17 (matrix protein, MA), p7 (nucleoprotein, NC), and p6 involved in the virus particle release. The pol gene encodes the Pr160GagPol precursor of the viral enzymes p10 (protease, PR), p51 (reverse transcriptase, RT), p15 (RNase H), and p32 (integrase, IN). The env gene encodes the PrGp160 precursor of the gp120 (surface glycoprotein, SU) and gp41 (transmembrane protein, TM). Other genes include tat, encoding p14 (transactivator protein), rev, encoding p19 (RNA splicing regulator), nef, encoding p27 (negative regulating factor), vif, encoding p23 (viral infectivity protein), vpr, encoding p15 (virus protein r), vpu, encoding p16 (virus protein unique), vpx in HIV2, encoding p15 (virus protein x), and tev, encoding p26 (tat/rev protein) [3]. The HIV infections are extremely problematic as the virus targets the CD4+ memory T-cells population, which is essential for organism immunity. HIV can attach itself to the host cell through 1) a relatively nonspecific interaction with negatively charged cell-surface heparan sulfate proteoglycans [4], 2) specific interactions between the Env and α4β7 integrin [5,6], and/or 3) the interaction with pattern-recognition receptors, such as the dendritic cell-specific intercellular adhesion molecular 3-grabbing non-integrin (DC-SIGN) [7]. The attachment of HIV in any of the abovementioned ways can increase the efficacy of infection because it brings Env, a heavily glycosylated trimer of gp120 and gp41 heterodimers, into close proximity with the viral receptor CD4 and co-receptor [8]. Finally, in order for the viral entry to occur, Env needs to bind itself to the host protein CD4 [9,10]. The binding of the HIV glycoprotein gp120 to the host cell CD4 receptor causes conformational changes of the gp120 glycoprotein, which uncover additional binding sites that interact with distinct proteins on the host cell membrane, known as β-chemokine co-receptors (mainly CCR5 and CXCR4), which facilitate the virus entry into the cell [11]. After the infection, a progressive decline of CD4 + cells consequently leads to the failure of the immune system function and the development of opportunistic infections that usually lead to death [1]. In HIV-infected patients, immunodeficiency develops both as a result of the viral replication and the failure of the patients’ homeostatic mechanisms. The continuous viral presence in the patients after the application of therapy is attributed to the CD4 + T-cell homeostasis owing to a pool of latently infected and resting CD4 + T-cells, macrophages, and follicular dendritic cells that remain in the organism. Indeed, the complex interactions of the patient’s immune system with the virus, and vice versa after the viral suppression, are thought to be crucial for the control of disease progression [12,13]. Current therapeutic approaches mainly target proteins that are vital for the viral cycle. One of the prominent examples is the linear 36-amino acid synthetic peptide enfuviritide (T20, Fuzeon), developed by Hoffmann-La Roche, and the first FDA approved fusion inhibitor for the treatment of HIV-1/AIDS acting through the binding to the gp41 subunit of the HIV-1 envelope glycoprotein. This induces a conformational change that brings the viral and cellular membranes into close enough proximity for the fusion and the subsequent viral entry into the host-cell to occur. Nevertheless, several restrictions, such as a low genetic barrier for drug resistance and a short in vivo half-life, limit its clinical use [14–17]. Other various FDA-approved antiretroviral drugs from seven mechanistic classes of inhibitors of the HIV replication are also available for the treatment of infected patients, namely, the nucleoside reverse-transcriptase inhibitors NRTIs, non-nucleoside reverse-transcriptase (RT) inhibitors NNRTIs, protein inhibitors PIs, fusion inhibitors, entry inhibitors—CCR5 co-receptor antagonists, HIV integrase strand transfer inhibitors, and multi-class combinations. None of the mentioned drug classes alone or in combination, the latter being known as the highly active antiretroviral therapy (HAART), can eradicate the HIV infection, and effective vaccines remain unavailable. The difficulties of HIV-1 vaccine research are, in part, a result of 1) the unavailability of a model for natural immunity related to HIV; 2) the existence of genetically distinct subtypes of HIV and frequent mutations; 3) unidentified correlates of specific immune response to HIV; 4) lack of a reliable, non-human animal model for HIV infection (SIV in monkeys vs. HIV in humans). Molecules 2019, 24, 3486 4 of 36

The established latent pro-viral reservoirs in the patient’s body can stochastically begin to reproduce viral particles, which makes the HIV disease practically incurable. From over 160 compounds identified so far as latency-reversing agents (LRAs), none have led to a promising cure [18]. Several rare and long-term remissions of HIV cases are described in the literature. For example, Berlin, London, and Düsseldorf’s patients underwent bone marrow transplantation with stem cells from a donor with a rare genetic mutation of the CCR5. The Mississippi baby received a very early antiretroviral therapy that extended the time of the viral rebound for more than 27 months. There undoubtedly remains a lot to be learned from these cases, and further investigation of stem-cell transplantation in people living with HIV is required [19–21]. The currently used antiretroviral treatment, alone or in combination, extends the quality and life expectancy of HIV-infected individuals but does not cure them. Drug resistance, along with the emergence of drug-resistant virus strains, a high-cost of the lifetime treatment regimen, cell toxicity, and serious side effects of currently used anti-HIV drugs [2] underlie the need for a synthetic development of new drugs or the search for active anti-HIV molecules in natural sources. Mother Nature has been perfecting its chemistry for three billion years, and most of it has been done in water. Intense competition and feeding pressure as well as non-static marine environmental conditions yield compounds with chemical and structural features generally not found in terrestrial natural products. New efficient molecules directed against HIV should demonstrate better performance in comparison with the currently approved drugs and suppress the HIV virus and/or eliminate the latent HIV reservoirs present in the human body. Around 60% of drugs currently available on the market are derived or inspired by nature [22]. Turning to nature for drug development holds great potential, especially when it comes to marine organisms. Only few marine-derived drugs have been approved on the market so far but many are in the preclinical or clinical stage of development [23]. Marine organisms make up to two-thirds of Earth’s species and produce, as a consequence of living in a highly competitive environment, unique and structurally diverse metabolites. Over the last 40 years, bioprospecting efforts have resulted in over 20,000 compounds of marine origin. The highest share of marine metabolites (up to 70%) are obtained from marine sponges, corals, and microorganisms, while mollusks, ascidians, and algae metabolites form only a minor part [24]. Oceans are, indeed, still a rather underexploited habitat, and biodiversity appears to be higher in the oceans than on land, which might be relevant when focusing on the marine environment as an untapped reservoir of novel antiretroviral candidates. In the discovery of new antiviral marine-derived drugs, researchers usually implement two strategies. They either screen the extracts from different strains (e.g., cyanobacteria, microalgae) or search directly for bioactive molecules in organisms—extract and purify them for evaluation within the drug development pipeline. It is thought that the marine environment might yield more potent anti-HIV candidates characterized by a higher efficiency (lower effective dose) and a better selectivity and which do not induce resistance development. This could, of course, only be speculation based on some of the previous success stories in the discovery of drugs from natural sources such as, e.g., lovastatin and paclitaxel. However, nature generally does create more sophisticated and perfected systems with a complex mode of action. An excellent example is protein lectin, derived from marine red algae Griffithsia sp. named Griffithsin with mid-picomolar activities, which groups it among the most potent HIV entry inhibitors reported so far [25]. It inhibits the HIV infection by binding itself to high mannose glycan structures on the surface of gp120, altering the gp120 structure or its oligomeric state [26]. This interaction relies on the specific trimeric “sugar tower,” including N295 and N448 [27]. Griffitshin can also prevent infections caused by other glycoprotein-enveloped viruses such as the Ebola virus, hepatitis C virus, and the severe acute respiratory syndrome coronavirus. It has been shown that the dimerization of Griffithsin is necessary for a high potency inhibition of HIV-1 [28]. However, the discrepancy between the HIV gp120 binding activity and the HIV inhibitory activity points to the presence of mechanism unrelated to a merely simple HIV gp120 binding [26]. The most promising application of Griffithsin Molecules 2019, 24, 3486 5 of 36 would be its incorporation into vaginal and rectal gels, creams, or suppositories acting as an antiviral microbicide to prevent the transmission of HIV. Despite the vast number of structurally diverse and unique bioactive molecules from the marine environment, the global marine pharmaceutical pipeline includes only eight approved drugs: Adcetris®, Cytosar-U®, Halaven®, Yondelis®, Carragelose®, Vira-A®, Lovaza®, and Prialt® [29]. Overall, it has taken 20 to 30 years from their discovery to their entry into the market. A sustainable supply, structural complexity, optimization of formulation, and ADMET properties, and a scale-up issue have prevented further development of several highly promising marine compounds. It is by no means an easy task to identify a marine candidate that may be considered as a potential drug. Initial high costs of developing a natural product into a drug could be balanced out with careful long-term considerations (biodiversity, supply, and technical, market) [30]. This paper provides an overview of natural marine metabolites that were first identified in the period between 2013 and 2018 or the previously identified marine constituents with a recently confirmed anti-HIV activity that could be potentially used or further optimized as novel ant-HIV agents. We also comprehensively summarize anti-HIV activities for several categories of marine structures including chitosan and its derivatives, sulfated polysaccharides, lectins, bromotyrosine derivatives, peptides, alkaloids, diterpenes, phlorotannins, and xanthones as well as fish oil as an auxiliary to HAART therapy.

2. Marine Compounds in the Treatment of HIV/AIDS

2.1. Chitosan and Its Derivatives Chitosan (2, Figure2), a natural marine byproduct, is a poly-cationic linear polysaccharide derived from chitin (1, Figure2) after partial deacetylation. Chitin is a structural element in the exoskeleton of mainly shrimps and crabs and is mainly composed of the randomly distributed β-(1-4)-linked D-glucosamine and N-acetyl-D-glucosamine. It has been previously shown that this compound can exhibit a large scale of different bioactivities and can also be used as a carrier for anti-HIV drugs [31]. Chitosan is loaded with saquinavir, an anti-HIV drug with a protease inhibitory activity, which showed better cell targeting efficiency than saquinavir alone [32]. Furthermore, trimethyl chitosan has improved Atripla, an anti-HIV drug consisting of efavirenz, emtricitabine, and tenofovir disoproxil fumarate, anti-HIV 1 activity, and has allowed it to be used in lower concentrations [33]. The antiretroviral activity is manifested in the chitosan-specific cationic nature that allows the formation of electrostatic complexes or multilayer structures with other negatively charged polymers [34]. Karagozlu et al. reported about new QMW-COS and WMQ-COS oligomers with anti-HIV activities. These oligomers are conjugates of chitosan and the Gln-Met-Trp peptide, which were constructed as a continuation of the authors’ previous research, in which a high potency of synthetically constructed chitosan oligomers was confirmed in anti-HIV therapy. More specifically, it was shown that these oligomers suppress syncytium formation, which occurs as a fusion of infected cells with neighboring cells, induced by HIV in a dose-dependent manner. However, the authors also noticed that after a certain period, the number of syncytia once again increased, suggesting that the cells should be re-treated with QMW-COS and WMQ-COS oligomers to maintain the primary therapeutically-relevant effect. The inhibition of the HIV-1 induced lytic effect, determined by the cell viability assay, showed that IC50 for QMW-COS was 48.14 µg/mL and was almost identical for WMQ-COS, 48.01 µg/mL. These oligomers effectively reduced the HIV load but showed no effects on HIV-1 RT and protease in vitro. Higher dosages were also required for the reduction in the HIV-1IIIB p24 antigen production assessed by the ELISA assay and the HIV-1RTMDR p24 antigen production. The highest difference between the compounds was reflected in IC50 values obtained from studies on the virus-induced luciferase activity in infected cells, where QMW-COS had a higher potency in comparison with WMQ-COS. Lastly, the authors determined the effects of oligomers on the interaction between gp41 and CD4 by using the CD4-gp41 ELISA assay, whereby both oligomers showed high potency. The effect of these oligomers was highest when they MoleculesMolecules2019 2019, 24, 24, 3486, x FOR PEER REVIEW 6 of 640 of 36

Molecules 2019, 24, x FOR PEER REVIEW 6 of 40 applied immediately upon the HIV-1 infection of cells, indicating that they should be used as a were applied immediately upon the HIV-1 infection of cells, indicating that they should be used as a potentialapplied treatmentimmediately in theupon early the stages HIV-1 of infection HIV infection, of cells, probably indicating at thatthe entrythey shouldstage [31]. be used as a potential treatment in the early stages of HIV infection, probably at the entry stage [31]. potential treatment in the early stages of HIV infection, probably at the entry stage [31].

CH3 HOH O CH3 OH OH HOH O NH OH O HO O OH OH O NH HO O O HO O O OH HOO O O HOHO O O O NH O O HO HO O HO NH2 O HO O OH NH OH HO NH2 O NH2 HOn NHOH O OH NH2 2 CH3 n NH2 CH n 3 n 1 2 1 2

FigureFigure 2. 2. ChemicalChemical structures of of chitin chitin (1 (1) )and and chitosan chitosan (2 ().2 ). Figure 2. Chemical structures of chitin (1) and chitosan (2). 2.2. Sulfated Polysaccharides 2.2.2.2. Sulfated Sulfated Polysaccharides Polysaccharides Sulfated polysaccharides (SP) are the most studied class of antiviral polysaccharides that are SulfatedSulfated polysaccharides polysaccharides (SP)(SP) are the mostmost studiedstudied class class of of antiviral antiviral polysaccharides polysaccharides that that are are structural components of the alga cell wall where they play both the storage and structural role. structuralstructural components components of of the the alga alga cellcell wall wherewhere th theyey play play both both the the storage storage and and structural structural role. role. They They Theyareare arean an animportant important important source source source ofof galactans, ofgalactans, galactans, commercia commerciallyllylly knownknown known as as agar agar as agarand and carrageenan and carrageenan carrageenan in inred redin alga red alga alga (Rhodophyta),(Rhodophyta),(Rhodophyta), fucans fucans fucans (fucoidan, (fucoidan,(fucoidan, sargassan,sargassan,sargassan, ascoasco ascophyllan,phyllan,phyllan, and and and glucuronoxylofucan) glucuronoxylofucan) glucuronoxylofucan) in inbrown inbrown brown alga alga alga (Phaeophyta),(Phaeophyta),(Phaeophyta), and and and ulvans-sulfated ulvans-sulfated ulvans-sulfated heteropolysaccharidesheteropolysaccharidesheteropolysaccharides that that that contain contain contain galactose, galactose, galactose, xylose, xylose, xylose, arabinose, arabinose, arabinose, mannose,mannose,mannose, glucuronic glucuronic glucuronic acid, acid, acid, or oror glucose glucoseglucose [[35–37].35–37]. ManyMany studies studies studies indicate indicate indicate that, that, that, in inmarine in marine marine algae, algae, algae, sulfated sulfated sulfated polysaccharidespolysaccharidespolysaccharides facilitate facilitate facilitate water waterwater and andand ionion retentionretention inin in extracellularextracellular extracellular matrices, matrices, matrices, which which which is anis is animportant an important important mechanismmechanismmechanism for for copingfor coping coping with with with desiccation desiccationdesiccation and and osmotic osmotiosmotic stressc stress stress in in in a a highly ahighly highly saltedsalted salted environment environment [38–40]. [38 [38–40].–40 ]. The antiviralTheThe antiviral antiviral activity activity ofactivity this groupof of thisthis of groupgroup compounds of compounds is mainly isis mainly connectedmainly connected connected to the degreeto to the the degree of degree sulfation, of ofsulfation, sulfation, constituent constituent sugars, molecular weight, conformation, and dynamic stereochemistry [41,42] . The effect sugars,constituent molecular sugars, weight, molecu conformation,lar weight, conformation, and dynamic and stereochemistry dynamic stereochemistry [41,42]. The [41,42] effect . The of effect counter of counter cation should also be considered as an important factor in observed biological activity. cationof counter should cation also beshould considered also be asconsidered an important as an factorimportant in observed factor in biologicalobserved biological activity. activity. The antagonizing effect of the negatively charged sulfated polysaccharides on the HIV-1 entry TheThe antagonizing antagonizing e effectffect ofof thethe negativelynegatively char chargedged sulfated sulfated polysaccharides polysaccharides on on the the HIV-1 HIV-1 entry entry intointo cells cells may may be be due due to to 1) 1) theirtheir bindingbinding ontoonto thethe positivelypositively charged charged V3 V3 domain domain of ofgp120, gp120, thereby thereby intopreventing cells may the be duevirus to attachment 1) their binding to the cell onto surface the [43–45] positively or 2) charged the masking V3 domainof the docking of gp120, sites therebyof preventing the virus attachment to the cell surface [43–45] or 2) the masking of the docking sites of preventinggp120 for the sCD4 virus on attachmentthe surface of to T thelymphocytes, cell surface thereby [43– 45disrupting] or 2) the the masking CD4-gp120 of interaction the docking [46– sites of gp120 for sCD4 on the surface of T lymphocytes, thereby disrupting the CD4-gp120 interaction [46– gp12048] for and sCD4 subsequently on the surface inhibiting of Tthe lymphocytes, expression of therebythe viral disruptingantigen and thethe CD4-gp120activity of the interaction viral reverse [46 –48] 48] and subsequently inhibiting the expression of the viral antigen and the activity of the viral reverse andtranscriptase subsequently [49,50]. inhibiting the expression of the viral antigen and the activity of the viral reverse transcriptase [49,50]. transcriptase [49,50]. 2.2.1. Heparan Sulfate 2.2.1. Heparan Sulfate 2.2.1. HeparanHeparinoid Sulfate polysaccharides can interact with the positive-charge regions of cell-surface glycoproteins,Heparinoid leading polysaccharides to a shielding can effect interact on thes withe regions, the whichpositive-charge prevents the regions binding of virusescell-surface to Heparinoid polysaccharides can interact with the positive-charge regions of cell-surface glycoproteins,the cell surface leading [51]. The to asulfated shielding polysaccharides effect on thes contente regions, in marinewhich preventsmollusks theis high binding in comparison of viruses to glycoproteins, leading to a shielding effect on these regions, which prevents the binding of viruses to the thewith cell the surface bovine [51]. mucosal The sulfated heparin polysaccharides (73.5%) and the porcinecontent mucosalin marine heparin mollusks (72.8%) is high [52]. in The comparison acidic cellwith surfacesulfate the bovinegroups [51]. The mucosalon sulfatedheparin heparin polysaccharides(3, Figure (73.5%) 3), and or contentheparin-likethe porcine in marine mucosalcompounds, mollusks heparin can is inhibit(72.8%) high inHIV [52]. comparison throughThe acidic with thesulfate bovineelectrostatic groups mucosal interactions on heparinheparin with (73.5%) (3 ,basic Figure andamino-acid 3), the or porcine heparin-likeresidues mucosal of the co heparintranscriptionalmpounds, (72.8%) can activator inhibit [52]. The TatHIV acidicprotein through sulfate groupselectrostatic[53]. on heparin interactions (3, Figure with3 ),basic or heparin-like amino-acid residues compounds, of the can transcriptional inhibit HIV activator through Tat electrostatic protein interactions[53]. with basic amino-acid residues of the transcriptional activator Tat protein [53].

Figure 3. Structure of heparan sulfate (3).

Molecules 2019, 24, x FOR PEER REVIEW 7 of 40

Figure 3. Structure of heparan sulfate (3). Molecules 2019, 24, 3486 7 of 36

2.2.2. Fucose Containing SP 2.2.2.So Fucose far, the Containing main anti-infectious SP activities documented for the fucose-containing SP are those againstSo far,viruses the main [54]. anti-infectious More importantly, activities these documented polysaccharides for the fucose-containing are selective inhibitors SP are those of various against virusesenveloped [54 ].viruses, More importantly,including HIV these [54–56]. polysaccharides FCSP acts during are selective the early inhibitors phase of ofinfection various by enveloped blocking viruses,the virus including attachment HIV and [54 entry–56]. into FCSP the acts host during cells, but the may early also phase inhibit of infection subsequent by blocking replication the stages virus attachmentin vitro [57]. and entry into the host cells, but may also inhibit subsequent replication stages in vitro [57].

2.2.3. Fucoidans Three fucoidansfucoidans extracted extracted from from three three brown brown seaweeds seaweeds (Sargassum (Sargassum mcclurei, Sargassummcclurei, polycystumSargassum, Turbinarapolycystum ornata, Turbinara) inhibit ornata the) early inhibit stages the early of HIV-1 stages entry of HIV-1 into target entry cells,into target with ICcells,50 ranging with IC50 from ranging 0.33 tofrom 0.7 0.33µM. to Neither 0.7 µM. the Neither sulfate the content sulfate nor content the position nor the of position sulfate of groups sulfate are groups related are to related the anti-HIV to the activityanti-HIV of activity fucoidans, of fucoidans, suggesting suggesting the involvement the involvement of other structural of other parametersstructural parameters such as the such molecular as the weight,molecular the weight, type of glycosidicthe type of linkage, glycosidic or evenlinkage, a unique or even fucoidan a unique sequence fucoidan [56 ].sequence Although [56]. the Although presence ofthe sulfo-groups presence of seemssulfo-groups to be necessary seems to for be anti-HIV necessary activity for anti-HIV [58], these activity data do[58], not these support data random do not sulfationsupport random as the main sulfation antiviral as the factor. main antiviral factor. Sulfated fucan polysaccharides,polysaccharides, ascophyllan (4, Figure4 4)) , and two fucoidans (S and A) ( 5 and 6, TableTable2 2),), derived derived from from di differentﬀerent sources,sources, signiﬁcantlysignificantly inhibitinhibit (IC(IC5050 1.3; 0.3; 0.6 µµg/mL)g/mL) the early step of HIV-1 (R9(R9 andand JR-Fl)JR-Fl) infection.infection. They also inhibit the VSV-G-pseudotype HIV-1 infectioninfection in HeLaHeLa cells [[59].59].

Figure 4. Structure of ascophyllan (4) andand fucoidanfucoidan unit.unit.

Table 2. Chemical composition of polysccharides (Fuc, Fucose; Xyl, Xylose; Glu, Glucose; Man, Table 2. Chemical composition of polysccharides (Fuc, Fucose; Xyl, Xylose; Glu, Glucose; Man, Mannose; Gal, Galactose) in ascophyllan, S- and A-fucoidan. Mannose; Gal, Galactose) in ascophyllan, S- and A-fucoidan.

NeutralNeutral Sugars sugars Fuc Xyl Glu Man Gal Uronic Acid SO Fuc Xyl Glu Man Gal Uronic acid SO3− 3− ascophyllanascophyllan (4) ( 15.54) 15.5 13.4 13.4 0.3 0.3 3.4 0.6 0.6 21.4 21.4 9.6 9.6 S-fucoidan S-fucoidan (5) 24.824.8 1.91.9 0.8 0.8 1 3.1 3.1 9.6 9.6 22.6 22.6 (5) A-fucoidan (6) 28.4 4.3 2.0 0.8 5.1 5.8 19.4 A-fucoidan 28.4 4.3 2.0 0.8 5.1 5.8 19.4 (6) Chondroitin sulfate with fucosylated branches (FuCS) (7, Figure5) has also attracted attention as anChondroitin HIV antiviral sulfate compound. with fuco Depolymerizedsylated branches fucosylated (FuCS) (7, CS, Figure extracted 5) has fromalso attracted the sea cucumber, attention hasas an shown HIV antiviralin vitro activitycompound. against Depolymerized a range of viral fucosylated strains, includingCS, extracted the resistantfrom the onessea cucumber, [60]. FuCS has is eshownffective in in vitro blocking activity the laboratoryagainst a strainrange HIV-1IIIBof viral strains, entry and including replication the byresistant inhibiting ones the [60]. p24 FuCS antigen is productioneffective in (4.26blocking and 0.73the laboratoryµg/mL, respectively) strain HIV- and1IIIB the entry infection and replication of the clinic by isolate inhibiting HIV-1KM018 the p24 andantigen HIV-1TC-2 production (23.75 (4.26 and and 31.86 0.73µg /µg/mL,mL, respectively) respectively) as well and as the suppressing infection of the the HIV-1 clinic drug-resistant isolate HIV- virus.1KM018 Additionally, and HIV-1TC-2 FuCS (23.75 is also and eff 31.86ective µg/mL, in T-20-resistant respectively) strains as well (EC50 as suppressing values ranging the HIV-1 from 0.76 drug- to 1.13resistantµg/mL). virus. The Additionally, depolymerized FuCS fragments is also effective seem to maintainin T-20-resistant a similar strains anti-HIV (EC50 action values at the ranging early stages from of0.76 infection, to 1.13 µg/mL). apparently The through depolymerized interaction fragments with an seem HIV envelopeto maintain glycoprotein a similar anti-HIV gp120. Theaction sulfated at the fucoseearly stages branches of infection, appear necessary apparently for through antiviral inte activity,raction which with is an also HIV affected envelope by molecular glycoprotein weight gp120. and carboxylationThe sulfated fucose [61]. While branches the in appear vitro results necessary of the for fucosylated antiviral activity, CS against which HIV is are also promising, affected it by is questionable whether the antiviral activity would be maintained in vivo. Other polyanionic HIV entry

Molecules 2019, 24, x FOR PEER REVIEW 8 of 40 molecularMolecules 2019 weight, 24, 3486 and carboxylation [61]. While the in vitro results of the fucosylated CS against8 HIV of 36 are promising, it is questionable whether the antiviral activity would be maintained in vivo. Other polyanionic HIV entry inhibitors, which advanced into clinical trials, failed to prove effective against theinhibitors, heterosexual which advancedHIV-1 transmission. into clinical trials,This failedwas related to prove to e ﬀfactorsective againstnot considered the heterosexual in previous HIV-1 developmenttransmission. stages, This was such related as the to presence factors not of consideredseminal plasma in previous and the development concentration stages, and retention such as the of presencepolyanionic of seminalinhibitors plasma [62]. and the concentration and retention of polyanionic inhibitors [62].

Figure 5. GeneralGeneral chemical structure of fucosylated chondroitin sulfate (7).

The complexcomplex chemical chemical architecture architecture and and the sulfatethe sulfate patterning patterning of marine of polysaccharidesmarine polysaccharides depends dependson numerous on factorsnumerous (species, factors tidal (species, cycles, environmentaltidal cycles, variationsenvironmental (e.g., salinity),variations harvesting (e.g., salinity), season, plantharvesting age, geographicalseason, plant location age, geographical etc.) [39,63 –location69], making etc.) isolation,[39,63–69], purification, making isolation, and comprehensive purification, andchemical comprehensive characterization chemical a highly characterization challenging taska highly [70]. challenging The development task [70]. of many The polysaccharidesdevelopment of manyinto clinical polysaccharides application isinto hindered clinical by application the still limited is hindered view of their by sophisticatedthe still limited and diverseview of nature. their sophisticatedDespite having and good diverse antiviral nature. effects, Despite the usehaving of carbohydrate good antiviral drugs effects, is still the in use its of infancy, carbohydrate and intensive drugs isstructure-activity still in its infancy, and and in vivointensive studies structure-activi are needed inty the and future. in vivo studies are needed in the future. A relatively new strategy in inducing immunity and developing an HIV vaccine is to use carbohydrates. TheThe major major di ffidifficultyculty of suchof such an approach an approach lies in mimickinglies in mimicking the specific the glycan specific protective glycan protectiveepitope. Gp120 epitope. of Gp120 HIV is of a highlyHIV is glycosylateda highly glycosylated envelope envelope surface glycoproteinsurface glycoprotein responsible responsible for the forreceptor the receptor and co-receptor and co-receptor binding, binding, which, together which, together with gp41, with comprises gp41, comprises the heterodimeric the heterodimeric envelope envelopetrimer spikes trimer of HIV.spikesN -linkedof HIV. glycans,N-linked mainly glycans, mannose mainly andmannose complex-type, and complex-type, cover much cover of the much gp120 of thesurface-accessible gp120 surface-accessible face of the face HIV of envelope the HIV spikeenvelope forming spike the forming glycan the shield. glycan Inadequate shield. Inadequate mimicry mimicryof the glycan of the shield, glycan tolerance shield, mechanisms,tolerance mechanisms, and/or the inabilityand/or the to induceinability a domain-exchangeto induce a domain- are exchangereflecting are diffi reflectingculties in difficulties creating the in proper creating specificity the proper of specificity Abs [71]. Most of Abs of [71]. the vaccines Most of the for HIV-1vaccines in preclinicalfor HIV-1 trialsin preclinical are based ontrials a Man areα 1-2Manbased on oligomannosyl a Manα1-2Man epitope oligomannosyl (various conjugates, epitope engineered (various yeastconjugates, strains, engineered and modified yeast glycoproteins) strains, and [72modified–79]. Better glycoproteins) specificity could[72–79]. potentially Better specificity be gained could using potentiallycarbohydrates be gained of marine using origin. carbohydrates of marine origin.

2.3. Lectins 2.3. Lectins Lectins are a group of proteins that specifically, but reversibly, bind glycosylated molecules Lectins are a group of proteins that specifically, but reversibly, bind glycosylated molecules on theon thecell cellsurface. surface. Precisely, Precisely, this thisgroup group of molecules of molecules can affect can a ffcell-cellect cell-cell interactions, interactions, protect protect cells from cells pathogens,from pathogens, influence influence cell celladhesion, adhesion, and and affect aff ectthe the intracellular intracellular glycoprotein glycoprotein translocation translocation [80]. [80]. Recently, lectinslectins have have become become promising promising agents agents for for antiretroviral antiretroviral therapy, therapy, and and different different researches researches have haveconfirmed confirmed their anti-HIV their anti-HIV properties. properties. Their antiretroviral Their antiretroviral activity is activity manifested is manifested through an alterationthrough an of alterationthe interaction of the between interaction HIV between gp120 orHIV gp41 gp120 and or the gp41 corresponding and the corresponding receptors [81 receptors], which, [81], in the which, end, ininhibit the end, the HIVinhibit cell the function, HIV cell HIV function, infectivity, HIV infe andctivity, the formation and the formation of the syncytium, of the syncytium, multi-nucleated multi- nucleatedcells [82–84 cells]. [82–84]. Several publishedpublished review review papers papers describe describe the previously the previously found marine found lectins marine with antiretrovirallectins with antiretroviralaction [85,86]. action For example, [85,86]. For Gogineni example, et al.Gogineni reported et aboutal. reported some about new, unusual some new, lectins, unusual such lectins, as the suchβ-galactose as the specificβ-galactose lectin specific (CVL), lectin CGL, (CVL), DTL, DTL-A, CGL, DTL, SVL-1, DTL-A, and SVL-2 SVL-1, [86 and]. Additionally, SVL-2 [86]. Additionally, Akkouh et al. Akkouhreported aboutet al. reported some new about algal some lectins, new such algal as Boodlea lectins, Coacta suchLectin, as Boodlea Griffi Coactathsin andLectin,Oscillatoria Griffithsin Agardhii and AgglutininOscillatoria (OAA),Agardhiiand Agglutinin some cyanobacterial (OAA), and lectins,some cyanobacterial such as Cyanovirin-N, lectins, such Scytovirin, as Cyanovirin-N, Microcystis ViridisScytovirin, Lectin, Microcystis and Microvirin. Viridis Lectin, and Microvirin. However, in the last few years, there has not been as much research focused on anti-HIV lectins from marine sources. Only Hirayama et al. (2016) reported about the new high-mannose specific lectin and its recombinants that possess anti-HIV activity [87]. In their research performed on the red Molecules 2019, 24, 3486 9 of 36 Molecules 2019, 24, x FOR PEER REVIEW 9 of 40

However, in the last few years, there has not been as much research focused on anti-HIV lectins alga Kappaphycus alvarezii, authors conﬁrmed KAA-1 and KAA-2, two KAA mannose-binding lectin from marine sources. Only Hirayama et al. (2016) reported about the new high-mannose specific isomers,lectin and as potent its recombinants anti-HIV that agents. possess The anti-HIV anti-HIV activity role of [87]. action In their of theseresearch two performed compounds on the includes red a strongalga bindingKappaphycus to the alvarezii, virus envelope authors confirmed glycoprotein KAA-1 gp120 and and, KAA-2, consequently, two KAA mannose-binding the inhibition of lectin HIV entry intoisomers, the host as cells.potent These anti-HIV KAA agents. recombinants, The anti-HIV as wellrole of as action the native of these one, two inhibited compounds the HIV-1includes entry a at IC50strongs (neutralization binding to the assay virus in envelope Jurkat cells) glycoprotein of 7.3–12.9 gp120 nM. and, Authors consequently, concluded the ininhibition the end of that HIV KAAs, besidesentry theirinto the strong host inhibitorycells. These e KAAﬀect onrecombinants, HIV entry intoas well the as cells, the native havea one, potential inhibited as agentsthe HIV-1 in treatmentsentry againstat IC50 others (neutralization viruses possessing assay in Jurkat high mannosecells) of 7.3– glycans12.9 nM. on Authors their envelope concluded as in well. the end that KAAs, besides their strong inhibitory effect on HIV entry into the cells, have a potential as agents in 2.4.treatments Peptides against other viruses possessing high mannose glycans on their envelope as well.

2.4.It Peptides has been shown that the majority of marine peptides have strong anti-HIV activity. They are usually isolated from marine organisms through the process of enzymatic hydrolysis [88]. The most commonIt sourcehas been of shown such constituents that the majority is marine of marine sponges peptides that are have known strong for anti-HIV their unique activity. metabolome They are [89] usually isolated from marine organisms through the process of enzymatic hydrolysis [88]. The most and are a source of more than 36% of all marine bioactive compounds [90]. Their bioactive peptides common source of such constituents is marine sponges that are known for their unique metabolome can be found in cyclic or linear forms and contain unusual amino acids that form unique structures [89] and are a source of more than 36% of all marine bioactive compounds [90]. Their bioactive rarelypeptides found can in be other found species. in cyclic Antiretroviral or linear forms activity and contain of such unusual structures amino worksacids that on form several unique different levels:structures blocking rarely of virusfound entry, in other inhibition species. of Antiretrov the cytopathiciral activity viral activity,of such structures neutralization works of on viral several particles, or inhibitiondifferent levels: of viral blocking fusion of and virus entry entry, [89 inhibition,91]. of the cytopathic viral activity, neutralization of viralRecently, particles, Shin or inhibition et al. discovered of viral fusion two and new entry depsipeptides [89,91]. from marine sponges Stelletta sp., stellettapeptinRecently, A Shin (8, Figure et al.6 ),discovered and stellettapeptin two new depsipeptides B ( 9, Figure6 ),from with marine the inhibition sponges of Stelletta the cytopathic sp., effectstellettapeptin of HIV-1 infectionA (8, Figure [92 6),]. and Confirming stellettapeptin the B mentioned (9, Figure 6), theory with the about inhibition the uniqueof the cytopathic metabolome of marineeffect of sponges,HIV-1 infection the authors [92]. Confirming revealed thatthe me thesentioned two theory compounds about the have unique previously metabolome undescribed of nonproteinogenicmarine sponges, amino-acid the authors parts revealed on peptides that these that two are rarelycompounds found have in nature. previously Namely, undescribed stellettapeptin A andnonproteinogenic stellettapeptin amino-acid B have an unexpectedparts on peptides polyketide that subunit, are rarely 3-hydroxy-6,8-dimethylnon-4-enoic found in nature. Namely, stellettapeptin A and stellettapeptin B have an unexpected polyketide subunit, 3-hydroxy-6,8- acid, 3-OHGln, and 3-OHAsn residues. Their high potency is witnessed through low EC50 values dimethylnon-4-enoic acid, 3-OHGln, and 3-OHAsn residues. Their high potency is witnessed (inhibition of the cytotoxic effect upon HIV infection)—values of 23 nM for stellettapeptin A and 27 nM through low EC50 values (inhibition of the cytotoxic effect upon HIV infection)—values of 23 nM for for stellettapeptin B. stellettapeptin A and 27 nM for stellettapeptin B.

FigureFigure 6. 6.Structures Structures of of stelletapeptin stelletapeptin (8 ()8 A) Aand and stelletapeptin stelletapeptin B (9 B). (9).

Furthermore,Furthermore, newly newly discovered discovered anti-HIV co constituentsnstituents derived derived from from marine marine sponges sponges VerongulaVerongula rigidarigidaand andAiolochoria Aiolochoria crassa crassa withwith amino-acid amino-acid structure structure were published were published by Gomez-Archila by Gomez-Archila et al. (2014) et al. (2014)[93]. [ In93 their]. In paper, their paper,they evaluated they evaluated and confirmed and confirmedthe anti-HIV the effect anti-HIV of 11 bromotyrosine effect of 11 derivatives bromotyrosine derivatives(Table 3), (Table whereby3), whereby aeroplysinin-1 aeroplysinin-1 (10), 19-deoxyfistularin ( 10), 19-deoxyfistularin 3 (15), purealidin 3 (15), purealidinB (16), fistularin B (16 ),3 fistularin(17) and 3-bromo-5-hydroxy-O-methyltyrosine (18, Figure 7) were the most potent in their anti-HIV 3 (17) and 3-bromo-5-hydroxy-O-methyltyrosine (18, Figure7) were the most potent in their anti-HIV activity. Aeroplysinin 1 (15) and purealidin B (16), compounds found in V. rigida species inhibited the activity. Aeroplysinin 1 (15) and purealidin B (16), compounds found in V. rigida species inhibited the HIV-1 replication in a dose-dependent manner by more than 50%. Specifically, for aeroplysinin 1, HIV-a replication was inhibited by 74% at a concentration of 20 µM, whereas purealidin was less MoleculesMolecules2019 2019, 24, 24, 3486, x FOR PEER REVIEW 10 of10 40 of 36

HIV-1 replication in a dose-dependent manner by more than 50%. Specifically, for aeroplysinin 1, potentHIV-a with replication inhibitory was power inhibited of 57%by 74% at a at concentration a concentration of 80of µ20M. µM, These whereas two compoundspurealidin was had less been previouslypotent with isolated; inhibitory however, power their of 57% anti-HIV at a concen activitytration was of proven 80 µM. in These this research. two compounds The same had was been with 3-bromo-5-hydroxy-previously isolated;O however,-methyltyrosine their anti-HIV (18) that activity has awas relatively proven highin this percentage research. The of inhibitionsame was with of HIV activity3-bromo-5-hydroxy- (47%) in a dose-dependentO-methyltyrosine manner. (18) that However, has a relatively the exact high mechanism percentage of action of inhibition remains of unclear.HIV Inactivity the same (47%) study, in a additional dose-dependent tests with manner. these However, compounds the exact on the mechanism HIV RT inhibition of action remains (qPCR of unclear. the early andIn latethe transcripts),same study, nuclearadditional import tests (qPCR with these analysis compounds of 2-LTR transcript),on the HIVand RT HIVinhibition entry inhibition(qPCR of the (viral infectivityearly and assay) late weretranscripts), performed. nuclear The import results showed(qPCR analysis that aeroplysinin-1 of 2-LTR transcript), (10), 19-deoxyfistularin and HIV entry 3 (15 ), purealidininhibition B (viral (16), fistularin infectivity 3 (assay)17), and were 3-bromo-5-hydroxy- performed. The resultsO-methyltyrosine showed that ( 18aeroplysinin-1) influenced the(10), nuclear 19- importdeoxyfistularin of the HIV 3 virus (15), withpurealidin around B or(16 more), fistularin than 50% 3 (17 of), inhibition: and 3-bromo-5-hydroxy- aeroplysinin-1O (10-methyltyrosine) showed 67% of (18) influenced the nuclear import of the HIV virus with around or more than 50% of inhibition: inhibition at 10 µM, 19-deoxyfistularin 3 62% inhibition at 20 µM, purealidin B 66% of inhibition at 20 µM, aeroplysinin-1 (10) showed 67% of inhibition at 10 µM, 19-deoxyfistularin 3 62% inhibition at 20 µM, fistularin 3 47% of inhibition at 10 µM, and 3-bromo-5-hydroxy-O-methyltyrosine 73% of inhibition at purealidin B 66% of inhibition at 20 µM, fistularin 3 47% of inhibition at 10 µM, and 3-bromo-5- 80 µM. Viral RT inhibition was not high for all compounds, whereby the highest results were around hydroxy-O-methyltyrosine 73% of inhibition at 80 µM. Viral RT inhibition was not high for all 50% of inhibition. For example, purealidin B had 58% of inhibition at 20 µM in the qPCR analysis of early compounds, whereby the highest results were around 50% of inhibition. For example, purealidin B transcripts.had 58% of As inhibition for the HIV at entry20 µM inhibition, in the qPCR all compoundsanalysis of early were transcripts. active in a dose-dependedAs for the HIV manner,entry withinhibition, the highest all compounds results of inhibition were active obtained in a fordose-depended 3,5-dibromo- manner,N,N,N,O with-tetramethyltyraminium the highest results of (13 ), frominhibition 14% to obtained 30%. Finally, for 3,5-dibromo- the authorsN stressed,N,N,O-tetramethyltyraminium the structural similarity (13 of), from these 14% compounds to 30%. Finally, with the HIVthe integrase authors stressed and protease the structural inhibitors, similarity suggesting of these that compounds these compounds with the HIV can integrase have a broader and protease mode of antiviralinhibitors, action. suggesting that these compounds can have a broader mode of antiviral action.

FigureFigure 7. 7. StructuresStructures of aeroplysinin-1aeroplysinin-1 ( (1010),), dihydroxyaerothionin dihydroxyaerothionin (11 (11), ),3,4-dibromo- 3,4-dibromo-N,N,NN,N,N- - trimethyltyraminiumtrimethyltyraminium ( 12(12),), 3,5-dibromo- 3,5-dibromo-N,N,N,O-tetramethyltyraminium-tetramethyltyraminium (13 (13), purealidin), purealidin R ( R14 (),14 19-), 19- deohxyﬁstularindeohxyfistularin 3 3 (15 (15),), purealidin purealidin BB ((1616), fistularin-3 ﬁstularin-3 ( (1717),), 3-bromo-5-hydroxy- 3-bromo-5-hydroxy-O-methyltyrosineO-methyltyrosine (18 (),18 ), 3-bromo-3-bromo-N,N,NN,N,N-trimethyltyrosinium-trimethyltyrosinium ((1919),), andand 3,5-dibromo-3,5-dibromo-N,N,NN,N,N-trimethyltyrosinium-trimethyltyrosinium (20 (20). ).

Molecules 2019, 24, x FOR PEER REVIEW 12 of 40

Table 3. Summary of anti-HIV compounds from marine organisms.

Refer Group Compound Location Organism Assay Dose Activity Structure ence

Molecules 2019, 24, x FOR PEER REVIEW 12 of 40

Table 3. Summary of anti-HIV compounds from marine organisms.

anti-HIV-1; Refer Group Compound Location Organism Assay Dose Activity Structure inhibition of ence IC50—inhibition of HIV-1 induced lytic effects 48.14 the HIV Molecules 2019, 24, 3486 (cell viability assay) µg/mL 11 of 36 entry at an IC50—inhibition of HIV-1IIIB p24 antigen 67.35 early stage, production (ELISA) µg/mL not blocking the marine IC50—inhibition of HIV-1RTMDR p24 antigen 81.03 QMW-COS Tabledisclosed 3. Summary a of anti-HIV compounds from marine organisms. fusion of + [31] byproduct production (ELISA) µg/mL anti-HIV-1;HIV-1 glutamine (Q), IC50—inhibition of virus-induced luciferase 68.13 Group Compound Location Organism Assay Dose Activityinhibitioninfected of methionine Structure (M), Reference IC50—inhibitionactivity in of infected HIV-1 inducedTZM-bl cellslytic effects µg/mL48.14 IC50—inhibition of HIV-1 induced lytic eﬀects thecells, HIV tryptophan (W) IC50—inhibition(cell viabilityof the interaction assay) between µg/mL39.13 (cell viability assay) Peptide + anti-HIV-1interferenceentry; inhibition at an IC —inhibition ofIC HIV-150gp41—inhibition andp24 CD4 antigenof (CD4-gp41 HIV-1IIIB p24 ELISA) antigen µg/mL67.35 chitosan 50 IIIB 48.14 µg/mL of the HIVofearly entrygp41-CD4 stage, at an production (ELISA)production (ELISA) µg/mL oligomer not 67.35 µg/mL early stage,blockingbinding blocking the marine IC marine—inhibition ofIC HIV-150—inhibitionp24 of HIV-1 antigenRTMDR p24 antigen 81.03 QMW-COS not disclosedQMW-COSa disclosed a 50 RTMDR 81.03 µg/mL the fusionfusion of HIV-1 of ++ [31][31 ] byproduct byproductproduction (ELISA)production (ELISA) µg/mL 68.13 µg/mL infectedHIV-1 cells, glutamine (Q), IC —inhibition of virus-induced luciferase activity 50 IC50—inhibition of virus-induced luciferase39.13 µg /mL 68.13 interference of methionine (M), in infected TZM-bl cells infected methionine (M), activity in infected TZM-bl cells µg/mLgp41-CD4 binding tryptophan (W) Peptide + IC —inhibition of the interaction between gp41 and cells, tryptophan (W) 50 IC50—inhibition of the interaction between 39.13 chitosan Peptide + CD4 (CD4-gp41 ELISA) interference gp41 and CD4 (CD4-gp41 ELISA) µg/mL oligomer chitosan IC50—Inhibition of HIV-1 induced lytic effects of gp41-CD4 IC50—Inhibition of HIV-1 induced lytic eﬀects oligomer (cell viability assay)(cell viability assay) 48.01 binding IC —inhibition ofIC50 HIV-1IIIB—inhibition p24 of antigen HIV-1IIIB p24 antigen µg/mL 50 48.01 µg/mL anti-HIV-1; production (ELISA)production (ELISA) 98.73 98.73 µg/mL anti-HIV-1inhibition; inhibition of marine not IC —inhibitionmarine ofIC HIV-150—inhibitionp24 of antigenHIV-1RTMDR p24 antigen µg/mL WMQ-COS not disclosedWMQ-COSa 50 RTMDR 144.02 µg/mL of the HIV entrythe HIV at an ++ [31][31 ] Molecules 2019, 24, x FOR PEERbyproduct REVIEWdisclosed a byproductproduction (ELISA)production (ELISA) 144.02 13 of 40 250 µg/mL earlyentry stage at an tryptophan (W) IC50—inhibition of virus-inducedIC50—inhibition luciferase of virus-induced activity luciferase µg/mL 51.48 µg/ml methionine (M), in infectedEC50—inhibition TZM-bl cells of HIV-1IIIB strain (syncytia early stage IC50—Inhibitionactivity in of infected HIV-1 inducedTZM-bl cellslytic effects 250 µg/mL glutamine (Q), IC —inhibition ofassay) interaction between gp41 and glutamine (Q), 50 IC50—inhibition(cell ofviability interaction assay) between gp41 51.4848.01 µg/ml CD4 (CD4-gp41EC50—inhibition ELISA) of HIV-1IIIB strain (p24 assay) IC50—inhibitionand CD4 (CD4-gp41of HIV-1IIIB ELISA) p24 antigen µg/mL EC50—inhibition of HIV-1IIIB/H9 strain (co- 0.24 µg/mL anti-HIV-1; EC50—inhibition of HIV-1IIIB strainproduction (syncytia (ELISA) assay) 98.73 cultivation assay) 0.73 µg/mL inhibition of not EC50—inhibitionmarine ofIC HIV-150—inhibitionIIIB strain of (p24 HIV-1 assay)RTMDR p24 antigen µg/mL WMQ-COS 50 RF µ the HIV + [31] discloseda byproductEC50—inhibition EC of—inhibition HIV-1IIIBproduction/H9 of strainHIV-1 (ELISA) strain (p240.24 assay)g/mL 4.26144.02 µg/mL (co-cultivationEC50—inhibition assay) of HIV-1KM018 strain0.73 (p24µg /mL1.14 µg/mL entry at an tryptophan (W) IC50—inhibition of virus-induced luciferase µg/mL anti-HIV-1; EC50—inhibition of HIV-1RF strain (p24assay) assay) 4.26 µg/mL 23.75 early stage methionine (M), EC —inhibition of HIV-1activitystrain in infected (p24 assay) TZM-bl cells1.14 µg/mL250 µg/mLanti-HIV-1 electrostatic; 50 EC50KM018—inhibition of HIV-1TC-2 strain (p24 µg/mL glutamine (Q), IC50—inhibition of interaction between gp41µ 51.48 µg/ml interactions heparan heparan sulfate not EC50—inhibition of HIV-1TC-2 strain (p24assay) assay) 23.75 g/mL 31.86 electrostatic Sulfated sulfate not disclosed - EC50—inhibitionof HIV-1A17andstrain CD4 (CD4-gp41 (p24 assay) ELISA) 31.86 µg/mL interactionswith with basic [53][53 ] (3) disclosed EC50—inhibition of HIV-1A17 strain (p24 µg/mL polysaccharides (3) EC50—inhibition of HIV-1RF/V82F/184V strain 1.09 µg/mL basic aminoamino acid acid assay) 1.09 µg/mL (p24 assay) 0.95 µg/mL residuesresidues of Tat of EC50—inhibition of HIV-1RF/V82F/184V strain (p24 0.95 µg/mL EC50—inhibition of HIV-1L10R/M461/L63P/V82T/184V 1.12 µg/mL Tat strain (p24 assay) assay) 71.76 µg/mL1.12 µg/mL EC50—inhibitionEC of50—inhibition HIV-1CBL-20 ofstrain HIV-1L10R/M461/L63P/V82T/184V97.63 µg /ml 71.76 (syncytia assay) strain (p24 assay) µg/mL97.63 EC50—inhibition of HIV-1ECROD50—inhibitionstrain (syncytia of HIV-1 assay)CBL-20 strain µg/ml (syncytia assay) Sulfated EC50—inhibition of HIV-1ROD strain (syncytia polysacchari assay) des anti-HIV-1; Sargassum inhibition of U373-CD4-CXCR4 cells 211 infected with mcclurei, the pseudotype viral Sargassum early phase IC50—inhibition (FSP crude extract)-(p24 Nha Trang polycystum 0.34 µg/mL of infection, fucose ELISA) bay, , and 0.39 µg/mL by blocking [56] containing IC50—inhibition (FTO crude extract)-(p24 Vietnam Turbinara 0.96 µg/mL the virus ELISA) Ornate attachment IC50—inhibition (FSM crude extract)-(p24 brown and entry ELISA) seaweeds into the host cells anti-HIV-1; early step of HIV-1 (R9 ascophyllan not different IC50—inhibition of HIV-1R9-real-time PCR 1.3 µg/mL and JR-Fl) [59] (4) disclosed sources infection;

inhibition of VSV-G-

Molecules 2019, 24, x FOR PEER REVIEW 13 of 40

EC50—inhibition of HIV-1IIIB strain (syncytia assay) EC50—inhibition of HIV-1IIIB strain (p24 assay) EC50—inhibition of HIV-1IIIB/H9 strain (co- 0.24 µg/mL cultivation assay) 0.73 µg/mL EC50—inhibition of HIV-1RF strain (p24 assay) 4.26 µg/mL EC50—inhibition of HIV-1KM018 strain (p24 1.14 µg/mL anti-HIV-1; assay) 23.75 electrostatic EC50—inhibition of HIV-1TC-2 strain (p24 µg/mL interactions heparan sulfate not assay) 31.86 - with basic [53] (3) disclosed EC50—inhibition of HIV-1A17 strain (p24 µg/mL amino acid assay) 1.09 µg/mL residues of EC50—inhibition of HIV-1RF/V82F/184V strain (p24 0.95 µg/mL Tat assay) 1.12 µg/mL EC50—inhibition of HIV-1L10R/M461/L63P/V82T/184V 71.76 strain (p24 assay) µg/mL97.63 EC50—inhibition of HIV-1CBL-20 strain µg/ml (syncytia assay) Molecules 2019, 24, 3486 Sulfated 12 of 36 EC50—inhibition of HIV-1ROD strain (syncytia polysacchari assay) des anti-HIV-1; Sargassum Table 3. Cont. inhibition of U373-CD4-CXCR4 cells 211 infected with mcclurei, the pseudotype viral Group Compound Location OrganismSargassum Assay Dose Activityearly phase Structure Reference IC50—inhibition (FSP crude extract)-(p24 Nha Trang polycystum 0.34 µg/mL of infection, fucoseSargassum ELISA) anti-HIV-1; inhibition mcclurei, bay, U373-CD4-CXCR4, and cells 211 infected with 0.39 µg/mL ofby the blocking [56] containing IC50—inhibition (FTO crude extract)-(p24 SargassumVietnam Turbinara pseudotype viral 0.34 µg/mL0.96 µg/mLearly phasethe virus of fucose Nha Trang bay, ELISA) polycystum, and IC50—inhibitionOrnate (FSP crude extract)-(p24 ELISA) 0.39 µg/mL infection,attachment by blocking [56] containing MoleculesVietnam 2019, 24, x FOR PEER REVIEW IC50—inhibition (FSM crude extract)-(p24 14 of 40 Turbinara IC50—inhibitionbrown (FTO crude extract)-(p24 ELISA) 0.96 µg/mL the virus attachmentand entry ELISA) Ornate brown IC50—inhibitionseaweeds (FSM crude extract)-(p24 ELISA) and entryinto into the thehost pseudotype seaweeds host cellscells d HIV-1 Molecules 2019, 24, x FOR PEER REVIEW anti-HIV-1anti-HIV-1; ; 14 of 40 infection in early stepearly of HIV-1step of HeLa cells (R9 andpseudotypeHIV-1 JR-Fl) (R9 ascophyllan ascophyllan not different infection;anti-HIV-1d HIV-1 ; not disclosed diﬀerent sources IC —inhibition ofIC HIV-150—inhibition-real-time of HIV-1 PCRR9-real-time 1.3PCRµg / mL 1.3 µg/mL and JR-Fl) [59][59 ] (4) (4) disclosed 50sources R9 inhibitionearly ofstep of infectioninfection; in VSV-G-pseudotypedHIV-1 (R9 inhibitionHeLa cells of HIV-1 infectionand JR-Fl) in fucoidan S IC50—inhibition of HIV-1R9-real-time PCR anti-HIV-1VSV-G- ; HeLainfection; cells (5) not different (fucoidan S) 0.3 µg/mL early step of anti-HIV-1inhibition; of [59] fucoidan A disclosed sources IC50—inhibition of HIV-1R9-real-time PCR 0.6 µg/ml HIV-1 (R9 early step ofVSV-G- HIV-1 (6) (fucoidan A) and JR-Fl) fucoidan S fucoidan S IC —inhibition ofIC HIV-150—inhibition-real-time of HIV-1 PCR R9-real-time PCR (R9 and JR-Fl) 50 R9 pseudotypeinfection; (5) (5) not different (fucoidan S) (fucoidan S) 0.3 µg/mL 0.3 µg/mL infection; not disclosed diﬀerent sources inhibitiond HIV-1 of [59][59 ] fucoidan A fucoidan A disclosed IC50sources—inhibition ofIC HIV-150—inhibitionR9-real-time of HIV-1 PCR R9-real-time0.6 PCRµg /ml 0.6 µg/mlinhibition infection of in 6 VSV-G- ( ) (6) (fucoidan A) (fucoidan A) VSV-G-pseudotypedHeLa cells HIV-1 infectionpseudotype in anti-HIV-1; HeLad cells HIV-1 inhibitioninfection in of EC50—HIV-1 p24 detection-PBMC assay- anti-HIV-1; inhibition chondroitin chondroitin EC50—HIV-1 p24 detection-PBMC assay-inhibition of HeLaHIV-1 cells not inhibition of HIV-1IIIB, HIV- 0.01–0.08of HIV-1 replication; sulfate not disclosed sulfate HIV-1IIIB, HIV-1 L10R/M46I/L63P/V82T/I84V, HIV-1A17, 0.01–0.08 µM replication; [61][61 ] disclosed 1L10R/M46I/L63P/V82T/I84V, HIV-1A17, HIV-1RF, and µM inhibitionanti-HIV-1; of the (7) (7) HIV-1RF, and HIV-1RF/V82F/184V strains inhibition of HIV-1RF/V82F/184V strains HIV-1inhibition entry of EC50—HIV-1 p24 detection-PBMC assay- chondroitin theHIV-1 HIV-1 red alga IC —neutralization assay in Jurkat cells (median not 50 inhibition of HIV-1IIIB, HIV- 0.01–0.08anti-HIV-1 ; inhibitionentry KAA-1 not disclosed sulfateKappaphycus tissue culture infectious dose (TCID50) method using 9.2 nM replication; [61][87 ] disclosed 1L10R/M46I/L63P/V82T/I84V, HIV-1A17, HIV-1RF, and µMof the HIV-1anti-HIV-1; entry (7) alvarezii Jurkat50 cells) inhibition of red alga IC —neutralizationHIV-1RF/V82F/184V assay strains in Jurkat cells not inhibitionthe HIV-1 of Lectins KAA-1 red alga IC —neutralizationKappaphyc assay(median in Jurkat tissue cells culture (median infectious dose 9.2 nM [87] disclosed 50 anti-HIV-1the; inhibitionentry HIV-1 KAA-2 not disclosed Kappaphycus tissue cultureus alvarezii infectious dose(TCID50) (TCID50) method method using using Jurkat cells)7.3 nM [87] of the HIV-1entry entry Lectins anti-HIV-1; alvarezii red alga JurkatIC50—neutralization cells) assay in Jurkat cells not inhibitionanti-HIV-1; of KAA-1 Kappaphycred alga IC(median50—neutralization tissue culture assay infectious in Jurkat dose cells 9.2 nM [87] disclosednot inhibitionthe HIV-1 of KAA-2 usKappaphyc alvarezii (median(TCID50) tissue method culture using infectious Jurkat cells) dose 7.3 nM [87] disclosed theentry HIV-1 Lectins us alvarezii (TCID50) method using Jurkat cells) anti-HIV-1;entry red alga IC50—neutralization assay in Jurkat cells not inhibition of KAA-2 Kappaphyc (median tissue culture infectious dose 7.3 nM [87] disclosed the HIV-1 us alvarezii (TCID50) method using Jurkat cells) entry

Molecules 2019, 24, 3486 13 of 36

Molecules 2019, 24, x FOR PEER REVIEW 15 of 40 Molecules 2019, 24, x FOR PEER REVIEW 15 of 40 Molecules 2019, 24, x FOR PEER REVIEW 15 of 40 Table 3. Cont. Molecules 2019, 24, x FOR PEER REVIEW 15 of 40 Group Compound Location Organism Assay Dose Activityanti-HIV-1; Structure Reference stellettapeptin north- marine anti-HIV-1;cytopathic EC50—inhibition of the cytotoxic effect upon anti-HIV-1; stellettapeptinA westernnorth- spongemarine 23 nm cytopathiceffect of [92] stellettapeptin north- marine EC50—inhibitionHIV-1 of the infection cytotoxic effect upon cytopathic A western sponge EC50—inhibition of the cytotoxic effect upon 23 nm anti-HIV-1;effect of [92] (A8) Australiawestern Stellettasponge sp . HIV-1 infection 23 nm effectHIV-1 of [92] stellettapeptin stellettapeptin (8) Australianorth- Stellettamarine sp . HIV-1 infection anti-HIV-1cytopathicinfectionHIV-1; north-western (8marine) spongeAustralia ECStelletta—inhibition sp. EC of the50—inhibition cytotoxic e offfect the upon cytotoxic effect upon HIV-1 A A western 50sponge 23 nm 23 nmcytopathic infectioneffect effect of of [92][92 ] Australia Stelletta sp. HIV-1 infection HIV-1 infection infection (8) Peptides (8) Australia Stelletta sp. HIV-1 infectionHIV-1 Peptides Peptides infection anti-HIV-1; Peptides north- marine anti-HIV-1;cytopathic Peptides stellettapeptin B EC50—inhibition of the cytotoxic effect upon anti-HIV-1; westernnorth- spongemarine 27 nm cytopathiceffect of [92] stellettapeptin(9) B north- marine EC50—inhibitionHIV-1 of the infection cytotoxic effect upon cytopathic stellettapeptin B western sponge EC50—inhibition of the cytotoxic effect upon 27 nm anti-HIV-1;effect of [92] (9) Australiawestern Stellettasponge sp . HIV-1 infection 27 nm effectHIV-1 of [92] stellettapeptin (9) Australianorth- Stellettamarine sp . HIV-1 infection anti-HIV-1cytopathicinfectionHIV-1; north-westernstellettapeptinmarine Bsponge Australia ECStelletta—inhibition sp. EC of the50—inhibition cytotoxic e offfect the upon cytotoxic effect upon HIV-1 B western 50sponge 27 nm 27 nmcytopathic infectioneffect effect of of [92][92 ] Australia (9) Stelletta sp. HIV-1 infection HIV-1 infection infection (9) (9) Australia Stelletta sp. HIV-1 infection HIV-1 infectionHIV-1 Australia Stelletta sp. 74% of HIV-1 infection inhibition74% of infection 74% of inhibitionat 20 µM % of inhibition of HIV-1 replication by flow inhibition 74% of at48%74% 20 µMof of anti-HIV-1; % of inhibition ofcytometry HIV-1 replication by flow at 20 µM % of inhibition of HIV-1 replication byinhibition flow at inhibition48% of anti-HIV-1; cytometry inhibition48% of inhibitionanti-HIV-1; of marine % of reverse transcription inhibition (qPCR20 µ M at 20 µM % of inhibition of HIV-1 replication by flowcytometry cytometry inhibitionatat 10 20 µM µM inhibitionHIV-1 of aeroplysinin-1 spongemarine % of reverseinhibitionanalysis transcription of of HIV-1 late transcripts) replication inhibition by (qPCR 48%flow of inhibition inhibition of Colombia% of reversemarine transcription % of reverse inhibition transcription (qPCR analysis inhibition (qPCR at67%48% 10anti-HIV-1 µMof of replication,anti-HIV-1;; inhibitionHIV-1 [93] aeroplysinin-1(10) Verongulasponge % of nuclearanalysis import cytometryof late inhibitiontranscripts) (qPCR inhibition at at 10 µM HIV-1 aeroplysinin-1 aeroplysinin-1marine spongeColombia sponge of late transcripts)analysis of late transcripts) inhibitioninhibition67%of of HIV-1 RT,inhibitionreplication, nuclear of [93] Colombia (10) Colombia Verongulamarinerigida % of% reverseofanalysis nuclear transcription ofimport 2-LTR inhibition transcript) inhibition (qPCR (qPCR10 µM 67% of replication, [93][93 ] (10) (10Verongula) rigida % of nuclearVerongula import inhibition% of nuclear (qPCR import analysis inhibition of (qPCR inhibitionatat 10 10 µM µMRT, nuclearimportRT,HIV-1 importnuclear and aeroplysinin-1 spongerigida analysisanalysis of of 2-LTR late transcripts) transcript) 67% of inhibition RT, nuclear Colombia rigida 2-LTR% of transcript) HIVanalysis entry inhibitionof 2-LTR transcript) (viral infectivity at67% 10 µM of andimportreplication, entry and [93] (10) Colombia Verongula % of nuclear import inhibition (qPCRinhibition at 67%dose of replication,entry [93] (10) % of HIVVerongula entry inhibition% of% HIVof (viral nuclear entry infectivity importinhibitionassay) assay)inhibition (viral infectivity (qPCR at 10 µM import and Bromotyrosi % of HIV entry inhibition (viral infectivityµ dependentinhibitiondose RT,entry nuclear Bromotyrosi rigida analysis of assay)2-LTR transcript) 10 M dose entry Bromotyrosine assay) dose dependentmannerdependentat 10 µM 2– import and ne % of HIV entry inhibition (viral infectivity dependent derivativesne manner 2–20%manner20%dose 2– entry Bromotyrosiderivatives assay) manner 2– derivatives dependent20% Bromotyrosine 3,5-dibromo ne 3,5-dibromo- 20% ne 3,5-dibromo- marine mannerdose 2– derivatives -N,N,N,O- N,N,N,O- manner 2– anti-HIV-1; derivatives 3,5-dibromo-marine sponge spongemarine % of HIV entry inhibition (viral infectivitydose depended dependeddoseanti-HIV-1 ; inhibition tetramethyl Colombia tetramethylN,N,N,O- Colombia% of HIVmarine entry inhibition (viral infectivity assay) dose20% inhibitionanti-HIV-1; of [93][93 ] N,N,NVerongula,O- rigida Verongulasponge % of HIV entry inhibitionassay) (viral infectivitymanner 14–30%mannerdepended 14–of HIV-1anti-HIV-1; entry Tyraminium Tyraminium3,5-dibromo-tetramethyl Colombia sponge % of HIV entry inhibition (viral infectivity depended HIV-1inhibition entry of [93] tetramethyl Colombia Verongulamarinerigida assay) manner30%dose 14– inhibition of [93] (13) TyraminiumN,(N13,N) ,O- Verongula assay) manner 14– HIV-1anti-HIV-1; entry Tyraminium spongerigida % of HIV entry inhibition (viral infectivity depended30% HIV-1 entry tetramethyl(13) Colombia rigida 30% inhibition of [93] (13) % of reverseVerongulamarine transcription % of reverse inhibition transcription (qPCRassay) analysis inhibition35% (qPCR inhibition manner 14– anti-HIV-1; Tyraminium19-deoxy Verongula assay) manner35% 14– HIV-1 entry Tyraminium spongemarinerigida of early% of transcripts) reverseanalysis transcription of early transcripts) inhibition (qPCRat 20 µ M 30% inhibitionanti-HIV-1;HIV-1 entry of 19-deoxy fistularin19-deoxy(13) 3 Colombia marinerigida % of reverse transcription inhibition (qPCR inhibition35%30%anti-HIV-1 anti-HIV-1;; inhibition [93] 19-deoxy(13marine) sponge % of reverseVerongulasponge transcription % of reverse inhibitionanalysis transcription (qPCRof early analysis transcripts) inhibition11% (qPCR inhibition 35% inhibitionHIV-1 of fistularin 3 Colombia fistularin(15) 3 Colombia sponge analysis of early transcripts) inhibitionat 20 µMof HIV-1 inhibition replication, of [93][93 ] fistularinVerongula 3 rigidaColombia Verongulamarinerigida of late% of transcripts) reverseanalysis transcription of late transcripts) inhibition (qPCRat 20 µ M inhibition replication,anti-HIV-1;HIV-1 [93] (15) 19-deoxy(15) Verongula % of reverse transcription inhibition (qPCR at 2035% µMRT, nuclearHIV-1 import (15) % of nuclearspongerigida import inhibitionanalysisanalysis (qPCR ofof analysis earlylate transcripts) transcripts) of 62% inhibitionat 20 µM inhibitionreplication, of fistularin 3 Colombia rigida analysis of late transcripts) µ inhibition replication, [93] Verongula 2-LTR% of transcript) reverse transcription inhibition (qPCRat 20 M HIV-1 (15) at 20 µM rigida analysis of late transcripts) replication,

Molecules 2019, 24, x FOR PEER REVIEW 16 of 40

% of nuclear import inhibition (qPCR 11% RT, nuclear Molecules 2019, 24, x FOR PEER REVIEW analysis of 2-LTR transcript) inhibition import 16 of 40 at 20 µM % of nuclear import inhibition (qPCR 11%62% RT, nuclear inhibition Molecules 2019, 24, 3486 analysis of 2-LTR transcript) inhibition import 14 of 36 atat 20 20 µM µM 57%62% of inhibitioninhibition Table 3. Cont. at 20at µM80 % of inhibition of HIV-1 replication by flow µM58%57% of of Group Compound Location Organism Assaycytometry Doseinhibition Activity Structure Reference inhibition anti-HIV-1; % of reverse transcription inhibition (qPCR at 20 µM 57% of at 80 inhibition of marine analysis of early transcripts) 34% of % of inhibition of HIV-1 replication byinhibition flow atµM58% of HIV-1 purealidin B sponge % of reverse transcription inhibition80 (qPCRµM58% ofinhibition Colombia% of inhibition of HIV-1 replication by flowcytometry cytometry inhibition replication, [93] (16) Verongula analysis of late transcripts) inhibition at at 20 µM anti-HIV-1; % of reverse transcription% of reverse inhibition transcription (qPCR analysis inhibition (qPCR at 20 µM RT, nuclear 20 µM inhibition of marinerigida of early transcripts)% ofanalysis nuclear ofimport early inhibitiontranscripts) (qPCR 34%66%anti-HIV-1 of of ; inhibition 34% of importHIV-1 and purealidin B purealidinmarine B sponge % of reversesponge transcription % of reverse inhibitionanalysis transcription (qPCR of 2-LTR analysis transcript)inhibition (qPCR inhibitioninhibitionof HIV-1 replication, Colombia Colombia inhibition at replication,entry [93][93 ] (16) (16Verongula) rigida Verongula of late% transcripts) of HIVanalysis entry ofinhibition late transcripts) (viral infectivity atat 20 20 µM µMRT, nuclear import 20 µM % of nuclear import inhibition (qPCR analysisassay) of dose andRT, entry nuclear rigida % of nuclear import inhibition (qPCR66% of 66% of 2-LTR transcript) depended import and analysis of 2-LTR transcript) inhibition atinhibition % of HIV entry inhibition (viral infectivity assay) entry % of HIV entry inhibition (viral infectivity20 µ M mannerat 20 µM 2– assay) dose depended dose11% manner 2–11%depended24% of inhibition 24% of manner 2– % of reverse transcription inhibitioninhibition (qPCR at at11% 5 µM, anti-HIV-1; % of reverse transcription inhibition (qPCR analysis marine analysis of late transcripts) 5 µM, 24%47%anti-HIV-1 of of inhibition; inhibition of, of late transcripts) fistularin 3 fistularinmarine 3 sponge sponge % of nuclear import inhibition (qPCR47% of inhibitionof, HIV-1 RT,HIV-1 nuclear RT, Colombia Colombia% of nuclear import inhibition (qPCR analysis of inhibition [93][93 ] (17) (17Verongula) rigida Verongula analysis of 2-LTR transcript)inhibition at at 10 µM,import andnuclear HIV-1 Molecules 2019, 24, x FOR PEER REVIEW 2-LTR% of transcript) reverse transcription inhibition (qPCR at 5 µM, anti-HIV-1; 17 of 40 rigida % of HIV entry inhibition (viral infectivity10 µM, dose entryimport and % of HIVmarine entry inhibition (viralanalysis infectivity of late assay)transcripts) 47% of inhibition of, dose depended fistularin 3 sponge % of nuclear importassay) inhibition (qPCR inhibitiondepended47% of HIV-1 entryRT, Colombia manner 11–13% [93] (17) Verongula analysis of 2-LTR transcript) manneratinhibition 10 µM, 11– nuclear rigida % of HIV entry inhibition (viral infectivity47% of at dose8013% µM, import and inhibition at % of inhibition of HIV-1assay) replication by flow depended54% of HIV-1 entry 80 µM, cytometry mannerinhibition 11– % of inhibition of HIV-1 replication by flow cytometry 54% of anti-HIV-1; % of reverse transcription inhibition (qPCR at 16013% µM, % of reverse transcription inhibition (qPCR analysis inhibition at inhibition of 3-bromo- marine analysis of early transcripts) 50% of 3-bromo- of early transcripts) 160 µM, anti-HIV-1; inhibitionHIV-1 5-hydroxy-O- 5-hydroxy-O-marine sponge % of reversesponge transcription % of reverse inhibition transcription (qPCR analysis inhibition (qPCR50% of inhibitionof HIV-1 replication, Colombia Colombia replication, [93][93 ] methyltyrosine methyltyrosineAiolochroia crassa Aiolochroia of late transcripts)analysis of late transcripts) inhibition at at 40 µM,RT, nuclear import RT, nuclear (18) (18) % of nuclearcrassa import inhibition% of nuclear (qPCR import analysis inhibition of (qPCR40 µM, 73% of and entry import and 2-LTR transcript)analysis of 2-LTR transcript) 73% of inhibition entry % of HIV entry inhibition% of HIV (viral entry infectivity inhibition assay) (viral infectivityinhibition at at 80 µM, µ assay) 80 M, dose dose depended depended manner 2–12% manner 2– 12% anti-HIV-1; inhibition of induced 459 µM syncytia (0.403 formation by EC50—against anti-HIV-1 induced cell lysis mg/mL) interference (MTT assay) 374 µM APCHP not Alaska of HIV EC50—HIV-1-induced RT activation in MT-4 (0.327 [94] (21) disclosed pollack fusion cells mg/mL) inhibition of EC50—against p24 production (western blot) 405 µM cell lysis, RT (0.356 activity and Peptides mg/mL) production of p24 antigen 0.691 mM anti-HIV-1; IC50—protective activity on HIV-1-induced (0.475 inhibition of cell lysis-MTT assay mg/mL) the HIV-1 not Spirulina % of RT Inhibition in HIV-1-infected cells 90% Leu-Asp-Ala-Val-Asn- SM-peptide RT activity [95] disclosed maxima (reverse transcriptase assay kit) inhibition Arg and p24 % of HIV-1 p24 antigen production (p24 at 1.093 antigen antigen production assay) mM (0.75 production mg/mL)

Molecules 2019, 24, x FOR PEER REVIEW 17 of 40

47% of inhibition at 80 µM, % of inhibition of HIV-1 replication by flow 54% of cytometry inhibition anti-HIV-1; % of reverse transcription inhibition (qPCR at 160 µM, inhibition of 3-bromo- marine analysis of early transcripts) 50% of HIV-1 5-hydroxy-O- sponge % of reverse transcription inhibition (qPCR inhibition Colombia replication, [93] methyltyrosine Aiolochroia analysis of late transcripts) at 40 µM, RT, nuclear (18) crassa % of nuclear import inhibition (qPCR 73% of import and analysis of 2-LTR transcript) inhibition entry % of HIV entry inhibition (viral infectivity at 80 µM, Molecules 2019, 24, 3486 assay) dose 15 of 36 depended manner 2– 12% Table 3. Cont. anti-HIV-1; inhibition of Group Compound Location Organism Assay Dose Activity Structure Reference induced 459 µM anti-HIV-1;syncytia inhibition (0.403of induced syncytia 459 µM formation by EC50—against anti-HIV-1 induced cell lysis mg/mL)formation by EC —against anti-HIV-1 induced cell lysis (0.403 mg/mL) interference 50 (MTT assay) 374 µMinterference of HIV APCHP APCHP not Alaska (MTT assay) 374 µM of HIV not disclosed Alaska pollack EC50—HIV-1-induced RT activation in MT-4 (0.327 fusion [94][94 ] (21) (21) disclosedEC —HIV-1-inducedpollack RT activation in MT-4 cells (0.327 mg/mL) fusion 50 cells mg/mL)inhibition of cell lysis, Molecules 2019, 24, x FOR PEER REVIEW EC50—against p24 production (western blot) 405 µM inhibition of 18 of 40 EC50—against p24 production (western blot) 405 µMRT activity and (0.356 mg/mL) cell lysis, RT (0.356production of p24 95% of antigenactivity and Peptides Peptides mg/mL) Molecules 2019, 24, x FOR PEER REVIEW inhibition production 18 of 40 0.691 mM at 1.093 (0.475 mg/mL) of p24 IC —protective activity on HIV-1-induced cell mM (0.75 50 90% inhibition 95% of antigen lysis-MTT assay mg/mL)anti-HIV-1 ; inhibition at 1.093 mM 0.691inhibition mM % of RTmarine Inhibition in HIV-1-infected cells (reverse of the HIV-1anti-HIV-1; RT SM-peptide not disclosed Spirulina maxima IC50—protective activity on HIV-1-induced(0.75 mg /mL) at(0.475 1.093 Leu-Asp-Ala-Val-Asn-Arg [95] transcriptase assay kit) activityinhibition and p24 of fungus 95% of % of HIV-1 p24 antigen productioncell lysis-MTT (p24 antigen assay mMmg/mL) (0.75antigen production Yongxing Aspergillus inhibition at the HIV-1 not Spirulina production% of RT assay) Inhibition in HIV-1-infected cells mg/mL)90% Leu-Asp-Ala-Val-Asn- SM-peptide Island, niger 1.093 mM RT activity [95] disclosed maximamarine (reverse transcriptase assay kit) inhibition Arg (0.75 mg/mL) and p24 South SCSIO % of HIV-1 p24 antigen production (p24 at 1.093 fungus antigen aspernigrin C China Sea Jcw6F30 IC50—inhibitory effects on infection by Yongxing Aspergillus antigen production assay) mM4.7 µM (0.75 anti-HIV-1 [96] (22) Yongxing isolated CCR5-tropic HIV-1 SF162 in TZM-bl cells production Island, niger mg/mL) marine fungusIsland, from Yongxing Island, Aspergillus nigerSouth SCSIO aspernigrin South marine South China SeaaspernigrinSCSIO C Jcw6F30China Sea ICJcw6F30—inhibitory eICﬀects50—inhibitory on infection effects by on infection by C China Sea 50alga 4.7 µM 4.7 µM anti-HIV-1anti-HIV-1 [96][96 ] Yongxing Island, (22isolated) fromYongxing CCR5-tropicisolated HIV-1CCR5-tropic SF162 in TZM-bl HIV-1 cellsSF162 in TZM-bl cells (22) Sargassum South China Sea marine alga Island, from sp. Sargassum sp.South marine marine China Sea alga Sargassumfungus Yongxing Aspergillus Alkaloids sp. Alkaloids Island, niger marine fungus marine South SCSIO Yongxing Island, Aspergillus niger fungus malformin C South Chinamalformin Sea SCSIO C Jcw6F30China Sea ICJcw6F30—inhibitory IC eﬀ50ects—inhibitory on infection effects by on infection by Yongxing Aspergillus50 1.4 µM 1.4 µM anti-HIV-1anti-HIV-1 [96][96 ] (23) Yongxing isolated CCR5-tropic HIV-1 SF162 in TZM-bl cells (23) AlkaloidsYongxing Island, isolated fromIsland, CCR5-tropicniger HIV-1 SF162 in TZM-bl cells South China Sea marine algaIsland, from South SCSIO Sargassum spSouth. marine malformin C China Sea Jcw6F30 IC50—inhibitory effects on infection by China Sea alga 1.4 µM anti-HIV-1 [96] (23) Yongxing isolated CCR5-tropic HIV-1 SF162 in TZM-bl cells Sargassum Island, from sp. South marine deep-sea China Sea alga anti-HIV-1; sediment South Sargassum inhibitory eutypellazine E fungus IC50—anti-HIV bioassay-pNL4.3.Env-.Luc Atlantic sp. 3.2 µM effects [97] (24) Eutypella co-transfected 293T cells Ocean deep-sea against HIV- sp. MCCC anti-HIV-1; sediment 1 replication South 3A00281 inhibitory eutypellazine E fungus IC50—anti-HIV bioassay-pNL4.3.Env-.Luc Atlantic 3.2 µM effects [97] (24) Eutypella co-transfected 293T cells Ocean against HIV- sp. MCCC 1 replication 3A00281

Molecules 2019, 24, x FOR PEER REVIEW 18 of 40

95% of inhibition at 1.093 mM (0.75 mg/mL) marine fungus Yongxing Aspergillus Island, niger South SCSIO aspernigrin C China Sea Jcw6F30 IC50—inhibitory effects on infection by 4.7 µM anti-HIV-1 [96] (22) Yongxing isolated CCR5-tropic HIV-1 SF162 in TZM-bl cells Island, from South marine China Sea alga Sargassum sp. marine fungus Yongxing Aspergillus Alkaloids Island, niger South SCSIO malformin C China Sea Jcw6F30 IC50—inhibitory effects on infection by Molecules 2019, 24, 3486 1.4 µM anti-HIV-1 [96] 16 of 36 (23) Yongxing isolated CCR5-tropic HIV-1 SF162 in TZM-bl cells Island, from South marine China Sea alga Table 3. Cont. Sargassum Group Compound Location Organismsp. Assay Dose Activity Structure Reference

Molecules 2019, 24, x FOR PEER REVIEW deep-sea 19 of 40 deep-sea anti-HIV-1; sediment anti-HIV-1; eutypellazine sediment South inhibitory MoleculesSouth 2019 Atlantic, 24eutypellazine, x FOR PEER REVIEW E IC fungus—anti-HIV bioassay-pNL4.3.Env-.LucIC50—anti-HIV bioassay-pNL4.3.Env-.Luc inhibitory effects 19 of 40 E fungus EutypellaAtlantic 50 3.2 µM 3.2 µM anti-HIV-1;effects [97][97 ] Ocean (24) Eutypellaco-transfected 293Tco-transfected cells 293T cells against HIV-1 (24) Molecules 2019, 24, x FOR PEERsp. REVIEWMCCC Ocean deep-sea againstinhibitory HIV- 19 of 40 sp. MCCC IC50—anti-HIV bioassay-pNL4.3.Env-.Luc replication 3A00281 sediment anti-HIV-1;effects South co-transfected 293T cells 1 replication eutypellazine J 3A00281deep-seafungus 4.9 µM againstinhibitory HIV- Atlantic ICreactivation50—anti-HIV activity-In bioassay-pNL4.3.Env-.Luc vitro latent HIV anti-HIV-1; [97] (25) sedimentEutypella 80 µM 1 replication,effects OceanSouth deep-sea reactivatingco-transfected assay-flow 293T cytometry-based cells inhibitory eutypellazinedeep-sea J sp.fungus MCCC IC50—anti-HIV bioassay-pNL4.3.Env-.Luc 4.9 µM anti-HIV-1againstlatency ;HIV- Atlantic ICsediment—anti-HIV bioassay-pNL4.3.Env-.Lucreactivation activity-Inscreening vitro latent HIV effects [97] eutypellazine (25) sediment South Eutypella50 co-transfected 293T cells 80 µMinhibitory 1 replication, effects South Atlanticeutypellazine J Ocean 3A00281fungusco-transfected reactivating 293T cells assay-flow cytometry-based4.9 µM 4.9 µM againstreactivating HIV- J fungus EutypellaAtlantic sp. MCCC reactivation activity-In vitro latent HIV againstlatency HIV-1 [97][97 ] Ocean (25) reactivationEutypella activity-In vitro latent HIVscreening reactivating 80 µM 80 µM 1 replication,agent (25) sp. MCCC Ocean 3A00281 reactivating assay-flow cytometry-based replication,reactivating latency sp.assay-flow MCCC cytometry-based screening anti-HIVlatency 1; 3A00281 screening reactivatingagent agent 3A00281 decreasereactivating the anti-HIV 1; transcriptionagent decrease the debromo- Coral reefs S. carteri 30% of ofanti-HIV the HIV-1, 1; % of reduction of HIV-1 replication-cell- transcription hymenialdisine in the Red sponge inhibitionanti-HIV abrogatedecrease 1; decrease the [98] debromo- debromo- Coral reefs S. carteri based assay 30% of 30% ofthe transcriptionof the HIV-1, of Coral reefs in (26S.) carteri spongeSea extract % of reduction of HIV-1 replication-cell- at 13 µM transcriptionG2- hymenialdisine hymenialdisine in the Red% of reductionsponge of HIV-1 replication-cell-based assay inhibition atinhibitionthe HIV-1,abrogate abrogate the [98][98 ] the Red Sea debromo-extract Coral reefs S. carteri based assay 30% of ofcheckpoint the HIV-1, (26) (26) Sea extract % of reduction of HIV-1 replication-cell-13 µM at 13 theµM G2-checkpointG2- of hymenialdisine in the Red sponge inhibition abrogateof the cell the [98] based assay the cellcheckpoint cycle (26) Sea extract at 13 µM cycleG2- of the cell anti-HIVcheckpoint 1; cycle decreaseof the cell the anti-HIV 1; anti-HIVtranscription 1;cycle decrease decrease the Coral reefs S. carteri <40% of <40% theof transcriptionof the HIV-1, of Hymenialdisine Coral reefsHymenialdisine in S. carteri sponge % of reduction of HIV-1 replication-cell- anti-HIV 1; in the Red% of reductionsponge of HIV-1 replication-cell-based assay inhibition atinhibitionthe HIV-1,transcriptionabrogate abrogate the [98][98 ] (27) the Red Sea (27) extract based assay decrease the Coral reefs S. carteri µ <40% of of the HIV-1, Hymenialdisine Sea extract % of reduction of HIV-1 replication-cell-3.1 M at 3.1 theµM G2-checkpoint transcriptionG2- of in the Red sponge inhibitionthe cellabrogate cycle the [98] (27) Coral reefs S. carteri based assay <40% of ofcheckpoint the HIV-1, Hymenialdisine Sea extract % of reduction of HIV-1 replication-cell- at 3.1 µM G2- in the Red sponge inhibition abrogateof the cell the [98] (27) based assay checkpoint Sea extract at 3.1 µM cycleG2- of the cell 90% of anti-HIV-1;checkpoint cycle inhibition inhibitionof the cell of Coral reefs S. carteri % of inhibition - HIV-1 RT biochemical assay 90% of anti-HIV-1; Oroidin at >25 µM HIV-1cycle RT, in the Red sponge % of reduction of HIV-1 replication-cell- inhibition inhibition of [98] (28) Coral reefs S. carteri % of inhibition - HIV-1 RT biochemical assay 50%90% of reductionanti-HIV-1; of Oroidin Sea extract based assay at >25 µM HIV-1 RT, in the Red sponge % of reduction of HIV-1 replication-cell- inhibition inhibitionHIV-1 of [98] (28) Coral reefs S. carteri % of inhibition - HIV-1 RT biochemical assay 50% of reduction of Oroidin Sea extract based assay atat >2550 µM µM replicationHIV-1 RT, in the Red sponge % of reduction of HIV-1 replication-cell- inhibition HIV-1 [98] (28) 50% of reduction of Sea extract based assay at 50 µM replication inhibition HIV-1 at 50 µM replication

Molecules 2019, 24, x FOR PEER REVIEW 19 of 40

anti-HIV-1; deep-sea inhibitory IC50—anti-HIV bioassay-pNL4.3.Env-.Luc sediment effects South co-transfected 293T cells eutypellazine J fungus 4.9 µM against HIV- Atlantic reactivation activity-In vitro latent HIV [97] (25) Eutypella 80 µM 1 replication, Ocean reactivating assay-flow cytometry-based sp. MCCC latency screening 3A00281 reactivating agent anti-HIV 1; decrease the transcription debromo- Coral reefs S. carteri 30% of of the HIV-1, % of reduction of HIV-1 replication-cell- hymenialdisine in the Red sponge inhibition abrogate the [98] based assay (26) Sea extract at 13 µM G2- checkpoint of the cell cycle anti-HIV 1; decrease the transcription Molecules 2019, 24, 3486 17 of 36 Coral reefs S. carteri <40% of of the HIV-1, Hymenialdisine % of reduction of HIV-1 replication-cell- in the Red sponge inhibition abrogate the [98] (27) based assay Sea extract at 3.1 µM G2- Molecules 2019, 24, x FOR PEER REVIEW Table 3. Cont. checkpoint 20 of 40 of the cell Group Compound Location OrganismWoody Assay Dose Activitycycle Structure Reference Island 90% of anti-HIV-1; Molecules 2019, 24, x FOR PEER REVIEW 90% of O 20 of 40 (Yongxing, inhibition anti-HIV-1inhibition of 3-(phenetyl Coral reefs S. carteri % of inhibition - HIV-1 RT biochemicalinhibition assay at anti-HIV-1;; O Oroidin Coral reefs in OroidinS. carteri spongeHainan, % of inhibition - HIV-1 RT biochemical assay >25 µM at >25 inhibitionµM HIV-1 of HIV-1 RT, amino) inWoody the Red A.sponge aptos %% ofof inhibitionreduction agaiof HIV-1nst HIV-1 replication-cell- replication- 88% of inhibitory [98][98 ] (28) Moleculesthe 2019 Red, 24 Sea, x FOR(28 PEER) extract REVIEW % of reduction of HIV-1 replication-cell-based assay 50% of 50% ofRT, reductionreduction of of 20 of 40 China)Sea and extract based assay N demethyl(oxy) Island sponge anti-HIV-1 activity assay-cell-basedinhibition at inhibitionHIV-1 replicationHIV-1effects [99] Seven O N aaptamine (Yongxing, extract VSVG/HIV-1 pseudotyping system50 µM at 10 µM against HIV- 3-(phenetyl ConnectedWoody at 50 µM anti-HIV-1;replication O HN (29) Hainan, 1 replication amino) IsletsIsland in the A. aptos % of inhibition against HIV-1 replication- 88% of inhibitory China) and N O Woody Island (Yongxing, demethyl(oxy) South sponge anti-HIV-1 activity assay-cell-based inhibition effects O [99] 3-(phenetyl (Yongxing,3-(phenetyl Seven anti-HIV-1; N aaptamine ChinaHainan, Sea extract VSVG/HIV-1 pseudotyping system at 10 µM anti-HIV-1against ;HIV- amino) Hainan, China)amino) Connected% of inhibitionA. aptos against% HIV-1 of inhibition replication-anti-HIV-1 against HIV-1 replication-88% of 88% of inhibitory HN (29) A. aptosChina)Woody and inhibitory1 replication effects N demethyl(oxy) and Sevendemethyl(oxy) Islets in the activitysponge assay-cell-basedanti-HIV-1 VSVG activity/HIV-1 assay-cell-basedinhibition atinhibition effects [99][99 ] sponge extractSevenIsland against HIV-1 aaptamine Connected Isletsaaptamine South extract pseudotypingVSVG/HIV-1 system pseudotyping system 10 µM at 10 µM against HIV- N Connected(Yongxing, replication HN (29) in the South3-(isopentyl(29) China Sea 1anti-HIV-1; replication China Sea IsletsHainan, in the amino) Woody A. aptos % of inhibition against HIV-1 replication- 72.3% of inhibitory China)South and demethyl(oxy) Island sponge anti-HIV-1 activity assay-cell-based inhibition effects [99] ChinaSeven Sea Woody Islandaaptamine (Yongxing, extract VSVG/HIV-1 pseudotyping system at 10 µM against HIV- 3-(isopentyl (Yongxing,3-(isopentyl ConnectedWoody anti-HIV-1; (30) Hainan, anti-HIV-11 replication; amino) Hainan, China)amino) IsletsIsland in % the of inhibitionA. aptos against% HIV-1 of inhibition replication-anti-HIV-1 against HIV-1 replication-72.3% of 72.3% of inhibitory A. aptosChina) and inhibitory effects demethyl(oxy) and Sevendemethyl(oxy) (Yongxing,South activitysponge assay-cell-basedanti-HIV-1 VSVG activity/HIV-1 assay-cell-basedinhibition atinhibition effects [99][99 ] 3-(isopentylsponge extractSeven againstanti-HIV-1; HIV-1 aaptamine Connected Isletsaaptamine ChinaHainan, Sea extract pseudotypingVSVG/HIV-1 system pseudotyping system10 µM at 10 µM against HIV- amino) Connected A. aptos % of inhibition against HIV-1 replication- 72.3% of replicationinhibitory (30) in the South (30) China) and screening 1 replication demethyl(oxy) Islets in the sponge anti-HIV-1 activity assay-cell-based inhibition effects [99] China Sea Seven of aaptamine South extract VSVG/HIV-1 pseudotyping system at 10 µM against HIV- Connected previously (30) screeningChina of Sea 1anti-HIV-1; replication Islets in the isolated previously screening EC50—multi-cycle viral replication assay 0.015 µM inhibition of South EC50—multi-cycle viral replication assay 0.015 µM anti-HIV-1; isolated compoun Gag bengamide % inhibitionof of p24%Gag inhibitionproduction-of of p24 PBMC production-of PBMC>90% of >90% of inhibitionNF- ofκB- bengamidecompounds A Chinanot Sea ds A not disclosed previouslyassay-p24Gag wasassay-p24 quantifiedGag by was ELISA quantified by ELISAinhibition at inhibitionNF- κB-mediatedmediated [100][100 ] (31) (originallydisclosed screening(originally anti-HIV-1; (31) EC50—inhibitionisolated ofEC LTR50—inhibition promoter-driven of LTR gene promoter-driven0.3 µ M at 0.3 µMretroviral retroviral gene isolated from isolatedof EC50—multi-cycle viral replication assay 0.015 µM inhibition of compounexpression-LTR-basedgene expression-LTR-based reporter assays reporter assays0.17 µ M 0.17 µM expressiongene Molecules 2019, 24, x FOR PEERthe sponge REVIEWJaspis previouslyfrom the % inhibition of p24Gag production-of PBMC >90% of NF-κB- 21 of 40 bengamide A not ds anti-HIV-1;expression cf. coriacea) isolatedsponge assay-p24Gag was quantified by ELISA inhibition mediated [100] (31) disclosed (originally EC50—multi-cycle viral replication assay 0.015 µM inhibition of compounJaspis cf. EC50—inhibition of LTR promoter-driven at 0.3 µM retroviral screeningisolated % inhibition of p24Gag production-of PBMC >90% of NF-κB- bengamide A not coriaceads ) gene expression-LTR-based reporter assays 0.17 µM anti-HIV-1;gene haliclony- screening of fromof the assay-p24Gag was quantified by ELISA inhibition anti-HIV-1mediated; [100] haliclony-(31) disclosed (originally expressioninhibitory cyclamine A previously not previouslysponge EC50—inhibition of LTR promoter-driven at 0.3 µMinhibitory retroviral effects not disclosedcyclamine A + B EC —multi-cycleEC viral50—multi-cycle replication viral assay replication assay 3.8 µM 3.8 µM effects [100][100 ] + B isolateddisclosed isolated50 against HIV-1 (32) Jaspis cf. gene expression-LTR-based reporter assays 0.17 µM againstgene HIV- (32) compounds compounfrom the replication coriacea) 1expression replication spongeds Jaspis cf. coriacea) screening anti-HIV-1; of inhibitory keramamine C not previously EC5—multi-cycle viral replication assay 3.4 µM effects [100] (33) disclosed isolated against HIV- compoun 1 replication ds

anti-HIV-1; HIV-1 RT EC50—inhibitory Effects on Wild-Type inhibition and NNRTI-Resistant HIV-1 Replication: 8.4 µM sponge (inhibitory EC50—inhibition of VSVG/HIV-1wt 7.0 µM Xisha Xestospong effects on stachybotrin D EC50—inhibition of VSVG/HIV-1RT-K103N 23.8 µM Island, ia wild type [101] (34) EC50—inhibition of VSVG/HIV-1RT-L100I,K103N 13.3 µM China testudinari and five EC50—inhibition of VSVG/HIV-1RT-K103N,V108I 14.2 µM s NNRTI- EC50—inhibition of VSVG/HIV-1RT-K103N,G190A 6.2 µM resistant EC50—inhibition of VSVG/HIV-1RT-K103N,P225H HIV-1 strains) anti-HIV-1; - Atol das brown inhibition of dolabelladienol Rocas, in alga EC50—inhibition of the cytopathic effect of the Diterpenes A 2.9 µM Northeast Dictyota HIV-1-MT-2 cells—MTT method cytopathic [102] (35) Brazil pfaffii effect of HIV-1 anti-HIV-1; - Atol das brown inhibition of dolabelladienol Rocas, in alga EC50—inhibition of the cytopathic effect of the B 4.1 µM Northeast Dictyota HIV-1-MT-2 cells—MTT method cytopathic [102] (36) Brazil pfaffii effect of HIV-1

Molecules 2019, 24, x FOR PEER REVIEW 21 of 40 Molecules 2019, 24, x FOR PEER REVIEW 21 of 40

screening Molecules 2019, 24, x FOR PEER REVIEW anti-HIV-1; 21 of 40 screeningof haliclony- anti-HIV-1;inhibitory Molecules 2019, 24, x FOR PEER REVIEW not previouslyof 21 of 40 cyclaminehaliclony- A + B EC50—multi-cycle viral replication assay 3.8 µM inhibitoryeffects [100] disclosednot screeningpreviouslyisolated cyclamine(32) A + B EC50—multi-cycle viral replication assay 3.8 µM anti-HIV-1;againsteffects HIV- [100] Molecules 24 disclosed compounisolatedof 2019, , 3486 haliclony-(32) screening against1inhibitory replication HIV- 18 of 36 not previouslycompounds anti-HIV-1; cyclamine A + B of EC50—multi-cycle viral replication assay 3.8 µM 1 replicationeffects [100] haliclony- disclosed isolatedds inhibitory (32) not previously against HIV- cyclamine A + B compoun EC50—multi-cycle viral replication assay 3.8 µM effects [100] disclosed isolatedscreening Table 3. Cont. 1 replication (32) screeningds againstanti-HIV-1; HIV- compounof anti-HIV-1; of 1 replicationinhibitory keramamine C not previouslyds Group Compound Location Organism AssayEC5—multi-cycle viral replication assay Dose 3.4 µM Activityinhibitoryeffects Structure Reference[100] keramamine(33) C disclosednot screeningpreviouslyisolated EC5—multi-cycle viral replication assay 3.4 µM anti-HIV-1;againsteffects HIV- [100] (33) disclosed compounisolatedof screening against1inhibitory replication HIV- keramamine C not previouslycompounds anti-HIV-1; EC5—multi-cycle viral replication assay 3.4 µM 1 replicationeffects [100] (33)screening ofdisclosed isolatedof anti-HIV-1; keramamine ds againstinhibitory HIV- keramaminepreviously C not previously inhibitory effects C not disclosed ECcompoun—multi-cycleEC viral5—multi-cycle replication viral assay replication assay 3.4 µM 3.4 µM anti-HIV-1;effects [100][100 ] (33) isolateddisclosed isolated5 against1 replication HIV-1 (33) ds againstanti-HIV-1;HIV-1 HIV- RT compounds compoun EC50—inhibitory Effects on Wild-Type replication inhibitionHIV-1 RT EC50—inhibitory Effects on Wild-Type 1 replication ds and NNRTI-Resistant HIV-1 Replication: 8.4 µM anti-HIV-1;inhibition sponge and NNRTI-Resistant HIV-1 Replication: 8.4 µM (inhibitory sponge EC50—inhibition of VSVG/HIV-1wt 7.0 µM HIV-1(inhibitory RT Xisha Xestospong EC50—inhibitory Effects on Wild-Type effects on stachybotrin D EC —inhibitoryEC EffECects50—inhibition50—inhibition on Wild-Type of VSVG/HIV-1of VSVG/HIV-1RT-K103Nwt 23.87.0 µM µM anti-HIV-1;inhibition Island,Xisha Xestospong50 ia and NNRTI-Resistant HIV-1 Replication: 8.4 µM wildeffects type on [101] stachybotrin(34) D and NNRTI-ResistantECEC50—inhibition50 HIV-1—inhibition Replication: of of VSVG/HIV-1 VSVG/HIV-1RT-L100I,K103NRT-K103N8.4 µ M 13.323.8anti-HIV-1 µM HIV-1; HIV-1 RT RT Island, spongeia EC50—inhibitory Effects on Wild-Type (inhibitorywild type [101] China testudinari EC50—inhibition of VSVG/HIV-1wt 7.0 µM and five (34) EC —inhibitionEC50 of—inhibition VSVG/HIV-1 of VSVG/HIV-1RT-K103N,V108IRT-L100I,K103N7.0 µM 14.213.3inhibition µM inhibition (inhibitory XishaChina Xestospongtestudinari50 and NNRTI-Resistantwt HIV-1 Replication: 8.4 µM effectsand five on stachybotrin stachybotrinsponge D s EC50—inhibition of VSVG/HIV-1RT-K103N 23.8 µM NNRTI- Xisha Island, ECsponge50—inhibition ECEC of50 VSVG50—inhibition—inhibition/HIV-1RT ofof-K103N VSVG/HIV-1VSVG/HIV-1RT-K103N,G190ART-K103N,V108I23.8 µM 14.26.2 eµM µMffects on(inhibitory wild type D XestospongiaIsland, ias EC50—inhibition of VSVG/HIV-1wt 7.0 µM wildNNRTI- type [101][101 ] (34) EC50—inhibition of VSVG/HIV-1RT-L100I,K103Nµ 13.3 µM resistant China Xisha EC50Xestospong—inhibition ofEC VSVG50—inhibition/HIV-1RT- L100I,K103Nof VSVG/HIV-1RT-K103NRT-K103N,G190A13.3,P225HM 6.2 µM andeffects five on (34) stachybotrintestudinaris D China testudinari EC50—inhibition of VSVG/HIV-1RT-K103N 23.8 µM andresistantHIV-1 five Island, EC50—inhibitionia ofECEC VSVG5050—inhibition—inhibition/HIV-1RT- K103N,V108Iofof VSVG/HIV-1VSVG/HIV-1RT-K103N,V108IRT-K103N14.2,P225Hµ M 14.2 µMNNRTI-resistant wild type [101] s 50 RT-L100I,K103N NNRTI-HIV-1 (34) EC —inhibition ofEC VSVG50—inhibition/HIV-1 of VSVG/HIV-1RT-K103N,G190A6.2 µ M 13.3 µMHIV-1 strains)strains) China 50testudinari EC —inhibitionRT- K103N,G190Aof VSVG/HIV-1 6.2 µM and five EC50—inhibition of VSVG/HIV-1RT-K103N,V108I 14.2 µM resistantstrains) EC50—inhibition ofEC VSVG50—inhibition/HIV-1RT- K103Nof VSVG/HIV-1,P225H RT-K103N,P225H anti-HIV-1; - s NNRTI-HIV-1 Atol das brown EC50—inhibition of VSVG/HIV-1RT-K103N,G190A 6.2 µM anti-HIV-1;inhibition of - dolabelladienol resistantstrains) Rocas,Atol das in brownalga ECEC50—inhibition50—inhibition of ofVSVG/HIV-1 the cytopathicRT-K103N effect,P225H of anti-HIV-1inhibitionthe;- of dolabelladienolDiterpenesAtol das Rocas,dolabelladienolA 2.9 µM HIV-1 brown algaNortheastRocas, in EC Dictyota—inhibitionalga ofEC the50—inhibitionHIV-1-MT-2 cytopathic eof ffcells—MTTect the of cytopathic method effect of inhibitionanti-HIV-1;cytopathic ofthe the - [102] Diterpenes A Diterpenesin Northeast (35A ) 50 2.9 µM 2.9 µM strains) [102] Dictyota pfaffiAtolNortheasti Brazil das brownDictyotaHIV-1-MT-2pfaffii cells—MTTHIV-1-MT-2 method cells—MTT method cytopathicinhibitioncytopathic eeffectffect ofof of [102] (35) Brazil dolabelladienol(35) anti-HIV-1; - Rocas, in alga EC50—inhibition of the cytopathic effect of HIV-1 the Diterpenes A Brazil pfaffii 2.9 µM effectHIV-1 of NortheastAtol das Dictyotabrown HIV-1-MT-2 cells—MTT method inhibitioncytopathic of [102] dolabelladienol(35) anti-HIV-1;HIV-1 - Rocas,Brazil in algapfaffii EC50—inhibition of the cytopathic effect of effectthe of Diterpenes A Atol das brown 2.9 µM anti-HIV-1anti-HIV-1;inhibition;- of - dolabelladienol Atol das Rocas,dolabelladienol Northeast Dictyota HIV-1-MT-2 cells—MTT method cytopathicHIV-1 [102] Molecules 2019, 24, x FOR(35 PEER) brown REVIEW alga Rocas,Atol das in EC —inhibitionbrownalga ofEC the50—inhibition cytopathic eofffect the of cytopathic effect of inhibitioninhibition ofthe the of 22 of 40 B in NortheastdolabelladienolB Brazil 50pfaffii 4.1 µM 4.1 µM effect of [102] Dictyota pfaffiNortheastRocas,i in DictyotaHIV-1-MT-2alga cells—MTTEC50—inhibitionHIV-1-MT-2 method of cells—MTT the cytopathic method effect of cytopathicanti-HIV-1;cytopathic effectthe of - [102] (36) Brazil (36B ) 4.1 µM HIV-1 PraiaAtolNortheastBrazil dasdo brownDictyotapfaffii HIV-1-MT-2 cells—MTT method HIV-1inhibitioncytopathiceffect of of [102] dolabelladienol(36) anti-HIV-1;anti-HIV-1; - Rocas, in alga EC50—inhibition of the cytopathic effect of the B Velho,Brazil pfaffii 4.1 µM effectHIV-1 of Praia do Velho, Atol das brown inhibition of dolabelladienol AngraNortheast dos Dictyota HIV-1-MT-2 cells—MTT method anti-HIV-1cytopathic; inhibitionHIV-1 [102] Angra dos Reis, (36) brown algaRocas, in alga EC50—inhibition of the cytopathic effect of HIV-1the dolastane dolastaneB Reis,Brazil in theEC —inhibitionpfaffii ofEC HIV-150—inhibition replication-CXCR4-tropic of HIV-1 replication-CXCR4- 4.1 µMof HIV-1 replication,effect of in the south of CanistrocarpusNortheast 50 CanistrocarDictyota HIV-1-MT-2 cells—MTT method 0.35 µM 0.35 µM replication,cytopathic [103][102][103 ] (38) (3836) south of HIV-1–MTT methodtropic HIV-1–MTT method potent effectHIV-1 on HIV-1 Rio de Janeiro cervicornis Brazil pfaffiipus potenteffect effect of Rio de infectivity State, Brazil cervicornis onHIV-1 HIV-1 Janeiro infectivity State, Brazil

Praia do anti-HIV-1; Velho, brown inhibition of Angra dos alga HIV-1 dolastane Reis, in the EC50—inhibition of HIV-1 replication-CXCR4- Canistrocar 0.794 µM replication, [103] (39) south of tropic HIV-1–MTT method pus potent effect Rio de cervicornis on HIV-1 Janeiro infectivity State, Brazil Praia do Velho, brown

Angra dos alga anti-HIV-1; secodolastane Reis, in the Canistroca EC50—inhibition of HIV-1 replication-CXCR4- inhibition of diterpene 3.67 µM [103] south of rpus tropic HIV-1–MTT method HIV-1 (40) Rio de cervicorni replication Janeiro s State, Brazil anti-HIV-1; 8,10,18- brown inhibition of Atol das trihydroxy-2,6- alga EC50—inhibition of the cytopathic the Rocas reef, 6.16 µM [104,1 dolabelladiene Dictyota effect of HIV-1-MT-2 cells—MTT method cytopathic Brazil 05] (41) friabilis effect of HIV-1 Santa anti-HIV-1; Marta inhibition of oxygenated octocoral EC50—inhibition of HIV-1-Inhibition of the Bay the dolabellane Eunicea cytopathic effect of HIV-1-MT-2 cells—MTT 3.9 µM [106] (Colombian cytopathic (42) laciniata method Caribbean effect of Sea HIV-1

Molecules 2019, 24, x FOR PEER REVIEW 22 of 40 Molecules 2019, 24, x FOR PEER REVIEW 22 of 40 Praia do Molecules 2019, 24, x FOR PEER REVIEW Praia do anti-HIV-1; 22 of 40 Velho, anti-HIV-1; Velho, brown inhibition of Angra dos brown inhibition of PraiaAngra do dos alga HIV-1 dolastane Reis, in the alga EC50—inhibition of HIV-1 replication-CXCR4- anti-HIV-1;HIV-1 Molecules 2019, 24, x FORdolastane PEER REVIEW Reis, Velho, in the Canistrocar EC50—inhibition of HIV-1 replication-CXCR4- 0.35 µM replication, 22 of[103] 40 (38) south of Canistrocarbrown tropic HIV-1–MTT method 0.35 µM inhibitionreplication, of [103] (38) Angrasouth dos of pus tropic HIV-1–MTT method potent effect Rio de algapus potentHIV-1 effect dolastane Reis,PraiaRio in do dethe cervicornis EC50—inhibition of HIV-1 replication-CXCR4- on HIV-1 Janeiro Canistrocarcervicornis 0.35 µM anti-HIV-1;replication,on HIV-1 [103] (38) southVelho,Janeiro of tropic HIV-1–MTT method infectivity State, Brazil brownpus inhibitionpotentinfectivity effect of AngraState,Rio de Brazildos Praia do cervicornisalga onHIV-1 HIV-1 Molecules 2019, 24, 3486 dolastane Reis,JaneiroPraia in thedo EC50—inhibition of HIV-1 replication-CXCR4- anti-HIV-1; 19 of 36 Velho, Canistrocar 0.35 µM replication,infectivityanti-HIV-1; [103] (38) State,southVelho, Brazil of brown tropic HIV-1–MTT method inhibition of Angra dos brownpus potentinhibition effect of PraiaAngraRio de do dos alga HIV-1 dolastane Reis, in the cervicornisalga EC50—inhibition of HIV-1 replication-CXCR4- anti-HIV-1;on HIV-1 dolastane Reis,JaneiroVelho, in the Canistrocar EC50—inhibition of HIV-1 replication-CXCR4- 0.794 µM replication, [103] (39) south of Canistrocarbrown Tabletropic 3. Cont. HIV-1–MTT method 0.794 µM inhibitioninfectivityreplication, of [103] (39) State,Angrasouth Brazil dos of pus tropic HIV-1–MTT method potent effect Rio de algapus potentHIV-1 effect dolastane Reis,PraiaRio in do dethe cervicornis EC50—inhibition of HIV-1 replication-CXCR4- on HIV-1 Group Compound Location OrganismJaneiro Canistrocarcervicornis Assay Dose0.794 µM Activityanti-HIV-1;replication,on HIV-1 Structure Reference[103] (39) southVelho,Janeiro of tropic HIV-1–MTT method infectivity Praia do Velho, State, Brazil brownpus ipotentnhibitioninfectivity effect of AngraState,Rio de Brazildos anti-HIV-1; inhibition Angra dos Reis, brown algaPraia do cervicornisalga onHIV-1 HIV-1 dolastane dolastane Reis,JaneiroPraia in theECdo —inhibition ofEC HIV-150—inhibition replication-CXCR4-tropic of HIV-1 replication-CXCR4- of HIV-1 replication, in the south of CanistrocarpusVelho, 50 Canistrocarbrown 0.794 µM 0.794 µM replication,infectivity [103][103 ] (39) (39) State,southVelho, Brazil of brownHIV-1–MTT methodtropic HIV-1–MTT method potent effect on HIV-1 Rio de Janeiro cervicornisAngra dos algapus potentanti-HIV-1; effect secodolastane PraiaAngraRio de do dos alga infectivityanti-HIV-1; State, Brazilsecodolastane Reis, in the Canistrocacervicornis EC50—inhibition of HIV-1 replication-CXCR4- inhibitionon HIV-1 of diterpene Reis,JaneiroVelho, in the Canistrocabrown EC50—inhibition of HIV-1 replication-CXCR4- 3.67 µM inhibition of [103] diterpene south of rpus tropic HIV-1–MTT method 3.67 µM infectivityHIV-1 [103] Praia do Velho, (40) State,Angrasouth Brazil dos of algarpus tropic HIV-1–MTT method anti-HIV-1;HIV-1 secodolastane Angra dos Reis,secodolastane(40)brown algaRio de cervicorni replication Reis,PraiaRio in do detheEC —inhibitionCanistrocacervicorni ofEC HIV-150—inhibition replication-CXCR4-tropic of HIV-1 replication-CXCR4- anti-HIV-1inhibition;replication inhibition of diterpene in the south ofditerpeneCanistrocarpus Janeiro 50 s 3.67 µM 3.67 µM [103][103 ] southVelho,Janeiro of brownrpuss HIV-1–MTT methodtropic HIV-1–MTT method of HIV-1 replicationHIV-1 (40) Rio de Janeiro (40) cervicornisState, Brazil AngraState,Rio de Brazildos cervicornialga anti-HIV-1;replication State, Brazilsecodolastane anti-HIV-1; Reis,Janeiro in the Canistrocas EC50—inhibition of HIV-1 replication-CXCR4- inhibition of diterpene8,10,18- brown 3.67 µM inhibitionanti-HIV-1; of [103] 8,10,18- 8,10,18- AtolState,south Brazil ofdas brownrpus tropic HIV-1–MTT method inhibitionHIV-1 of trihydroxy- trihydroxy-2,6-(40) Atol das alga EC50—inhibition of the cytopathic anti-HIV-1the; inhibition Atol das Rocastrihydroxy-2,6-brown algaRocasRio dereef, ECcervicornialga—inhibition of the cytopathicEC50—inhibition effect of of the cytopathic 6.16 µM anti-HIV-1;replicationthe [104,1 2,6- dolabelladiene Rocas reef, Dictyota50 effect of HIV-1-MT-2 cells—MTT method6.16 µM 6.16 µMof thecytopathic [[104,1104,105] reef, Brazildolabelladiene8,10,18-Dictyota friabilisBrazilJaneiro brownDictyotaHIV-1-MT-2s cells—MTTeffect of HIV-1-MT-2 method cells—MTT method inhibitioncytopathic of 05] dolabelladiene (41) AtolBrazil das friabilis effecteffect of HIV-1 of 05] trihydroxy-2,6- State, Brazil alga EC50—inhibition of the cytopathic the (41) (41) Rocas reef, friabilis 6.16 µM HIV-1effect of [104,1 dolabelladiene Dictyota effect of HIV-1-MT-2 cells—MTT method anti-HIV-1;cytopathicHIV-1 BrazilSanta anti-HIV-1; 05] 8,10,18-(41) brownfriabilis inhibitioneffect of AtolMarta Santadas inhibitionanti-HIV-1; of oxygenated Santa Martatrihydroxy-2,6-oxygenated Marta algaoctocoral EC50—inhibitionEC50—inhibition of HIV-1- ofInhibition the cytopathic of the anti-HIV-1theHIV-1inhibition; inhibition of oxygenatedoctocoral RocasBay reef, EC50octocoral—inhibition ofEC HIV-1-Inhibition50—inhibition of ofHIV-1- the Inhibition of the 6.16 µM the [104,1 dolabellane Bay (Colombiandolabelladienedolabellane SantaBay DictyotaEunicea cytopathiceffect of HIV-1-MT-2 effect of HIV-1-MT-2 cells—MTT cells—MTT method3.9 µM 3.9 µMof thecytopathic cytopathicanti-HIV-1;the [106][106 ] Molecules 2019, 24, x dolabellaneFOR PEEREunicea REVIEW laciniataBrazil(Colombian cytopathic Eunicea effect of HIV-1-MT-2cytopathic cells—MTT effect of HIV-1-MT-2 method cells—MTT 3.9 µM cytopathic 23 of05][106] 40 (42) MoleculesCaribbean 2019, 24 Sea, x FOR(4142 PEER) REVIEW(Colombian Marta friabilislaciniata method effecteffectinhibition ofcytopathic HIV-1 ofof 23 of 40 oxygenated Caribbean octocoral EC50—inhibition of HIV-1-Inhibition of the effect of (42) Bay laciniata method HIV-1the dolabellane CaribbeanSea Eunicea cytopathic effect of HIV-1-MT-2 cells—MTT 3.9 µM HIV-1effect of [106] (ColombianSanta anti-HIV-1;cytopathic (42) SantaSea laciniata method anti-HIV-1;HIV-1 CaribbeanMarta inhibitioninhibitioneffect of ofof oxygenated octocoral EC50—inhibition of HIV-1-Inhibition of the oxygenated Santa Martaoxygenated Bay octocoral EC50—inhibition of the cytopathic effect of anti-HIV-1; inhibitionthe dolabellaneoctocoral BaySea ECEunicea—inhibition EC of50 the—inhibition cytopathic of e fftheect cytopathic of effect of 0.73 µM HIV-1the [106] dolabellane Bay (Colombiandolabellane 50Eunicea cytopathic effect of HIV-1-MT-2 cells—MTT0.73 µ M 0.733.9 µM µMof the cytopathic [106][106 ] Eunicea laciniata(Colombian(Colombian HIV-1-MT-2 cells—MTTHIV-1-MT-2 method cells—MTT method cytopathic (43) Caribbean Sea ((4243)) laciniatalaciniata method effect of HIV-1 Caribbean effect of Sea HIV-1 Sea HIV-1 Santa anti-HIV-1; Marta inhibition of oxygenated Santa Martaoxygenated Marta octocoral EC50—inhibition of HIV-1-Inhibition of the anti-HIV-1inhibition; inhibition of oxygenatedoctocoral Bay ECoctocoral—inhibition EC of50 HIV-1-Inhibition—inhibition of HIV-1- of the Inhibition of the the dolabellane Bay (Colombiandolabellane Bay 50Eunicea cytopathic effect of HIV-1-MT-2 cells–MTT0.69 µ M 0.69 µMof the cytopathicthe [106][106 ] dolabellaneEunicea laciniata(Colombiancytopathic Eunicea effect of HIV-1-MT-2cytopathic effect cells–MTT of HIV-1-MT-2 method cells–MTT 0.69 µM cytopathic [106] (44) Caribbean Sea (44) (Colombian laciniata method effect ofcytopathic HIV-1 (44) Caribbean laciniata method effect of Caribbean effect of Sea HIV-1

anti-HIV-1; inhibition of the Inhibition the Inhibition cytopathic in dose- cytopathic in dose- effects of depended effects of depended HIV-1: Inhibition of syncytia formation on C8166 manner * HIV-1: brown Inhibition of syncytia formation on C8166 manner * inhibition of brown cells (HIV-1IIIB, HIV-1RF and HIV-1LAI)- Cell inhibition of cells (HIV-1IIIB, HIV-1RF and HIV-1LAI)- Cell 8,4′′′′′′-dieckol not alga, syncytia inverted microscope viability [107] (45) disclosed Ecklonia formation, Inhibition of the cytopathic effect of HIV-1- was more cava lytic effects, C8166 cells—MTT method than 90% inhibition of dose- viral p24 dependent antigen inhibition production, HIV-1 entry inhibition

Molecules 2019, 24, x FOR PEER REVIEW 23 of 40

Santa anti-HIV-1; Marta inhibition of Molecules 2019, 24, xoxygenated FOR PEER REVIEW octocoral 24 of 40 Molecules 2019, 24, 3486 Bay EC50—inhibition of the cytopathic effect of the 20 of 36 dolabellane Eunicea 0.73 µM [106] (Colombian HIV-1-MT-2 cells—MTT method cytopathic (43) laciniata Inhibited and RT Caribbean effect of 91% inhibition Sea HIV-1 Table 3. Cont. activity of Santa anti-HIV-1; HIV-1IIIB RT Marta inhibition of Group Compound Locationoxygenated Organism octocoral EC Assay50—inhibition of HIV-1-Inhibition of Dosethe and Activity Structure Reference Bay the dolabellane Eunicea cytopathic effect of HIV-1-MT-2 cells–MTTInhibition inapproximat0.69 µM [106] (Colombian cytopathic (44) laciniata Effect on p24 antigenmethod production-p24 dose-depended antigen ely 80% for CaribbeanInhibition of syncytia formation on C8166 cells effect of capture ELISA and immunoblast analysismanner * rest of the (HIV-1 , HIV-1 and HIV-1 )-inverted Sea IIIB RF LAI Cell viability HIV-1 microscopeRT activity assay—commercial fluorescence HIV-1 was more than Inhibition of the cytopathic effect ofRT HIV-1-C8166 assay kit strains 90% anti-HIV-1; cells—MTT method tested, dose-dependent inhibition of HIV-1RTMDR1 inhibition the strainInhibition was Inhibited 91% cytopathic anti-HIV-1; inhibition activity of inhibitedin dose- at of the cytopathiceffects of HIV-1 RT dependeda ratio of IIIB effects ofHIV-1: Inhibition of syncytia formation onand C8166 approximat manner76.1% * Effect onbrown p24 antigen production-p24 antigen capture inhibitioninhibition of syncytia of cells (HIV-1IIIB, HIV-1RF and HIV-1elyLAI 80%)- for rest AtCell the 8,4 -dieckol 8,4′′′-dieckolbrown alga, not ELISAalga, and immunoblast analysis formation,syncytia lytic 000 not disclosed inverted microscope of the HIV-1 viability [107][107 ] (45) Ecklonia cava RT activity assay—commercial fluorescence RT highesteffects, inhibition of (45) disclosed Ecklonia strains tested, formation, Inhibitionassay kit of the cytopathic effect of HIV-1- concentratiwas moreviral p24 antigen cava HIV-1 lytic effects, C8166 cells—MTT method RTMDR1 thanon, 90% production, strain was inhibition of inhibitiondose-HIV-1 entry inhibition inhibited at a viral p24 Inhibition of HIV-1 replication- dependentwas moreand RT inhibition ratio of 76.1% antigen Luciferase gene reporter assay inhibitionthan 80% At the highest production, for all viral concentration, HIV-1 entry strains inhibition was inhibition Inhibition of HIV-1 replication-Luciferase gene more than 80%except for reporter assay for all viral RTMDR1 strains except (76.33%) for RTMDR1 anti-HIV-1; (76.33%) inhibition of from the anti-HIV-1; inhibition from the infection IC —inhibitionjellyfish- of PXAIC on50—inhibition infection by CCR5-tropicof PXA on infection by of infection against penicilli- penicilli-jellyfish-derived 50 against not derivedHIV-1 in TZM-blCCR5-tropic cells HIV-1 in TZM-bl cells0.36 µM 0.36 µMCCR5-tropic HIV-1 xanthone A Moleculesnot disclosed2019, 24, xxanthone FOR PEER Afungus REVIEW CCR5-tropic 25 of[108][ 10840 ] disclosed ICfungus—inhibition ofIC PXA50—inhibition on infection of PXA by on infection0.26 by µM 0.26 µM SF162 and (46) (46) Aspergillus 50 HIV-1 SF162 AspergillusCXCR4-tropic HIV-1CXCR4-tropic in TZM-bl HIV-1 cells in TZM-bl cells CXCR4-tropic HIV-1 fumigates andanti-HIV-1; CXCR4- fumigates NL4-3 neuroprotecttropic HIV-1 anti-HIV-1; iveNL4-3 effect on neuroprotectiveneuroinflam effect docosahexanoic docosahexanoic on not In vivo study on maleIn rat vivo models-Male study on male F344 rat (control) models-Male F344 mations acid not disclosed acid neuroinflammations [109][109 ] disclosed and HIV-1Tg(control) rats and HIV-1Tg rats induced by (48) (48) induced by ethanol ethanol (in (in the presence of HIV viralthe proteins) presence of HIV viral proteins) anti-HIV-1; Tutuila, EC50—In Vitro Model of HIV-1 Latency-high- reactivation radicicol H. American throughput primary cell-based HIV-1 latency 9.1 µM of latent [110] (49) fuscoatra Samoa assay viral loads in Phlorotannin CD4+ T-cells s and anti-HIV-1; xanthones Tutuila, EC50—In Vitro Model of HIV-1 Latency-high- reactivation pochonin B H. American throughput primary cell-based HIV-1 latency 39.6 µM of latent [110] (50) fuscoatra Samoa assay viral loads in CD4+ T-cells

Auxiliary anti-HIV-1; therapy to Tutuila, EC50—In Vitro Model of HIV-1 Latency-high- reactivation pochonin C H. HAART American throughput primary cell-based HIV-1 latency 6.3 µM of latent [110] (51) fuscoatra therapy— Samoa assay viral loads in fish oil CD4+ T-cells Yongxing sponge- anti-HIV-1; Island, associated H truncateol O IC50—Anti-HIV bioassays-VSV-G inhibition of Hainan fungus 39 µM [111] (52) pseudotyped HIV-1–Luciferase assay system the HIV OH Province of Truncatella replication HO H China angustata O Others Yongxing sponge- anti-HIV-1; Island, associated truncateol P IC50—Anti-HIV bioassays-VSV-G inhibition of Hainan fungus 16.1 µM [111] (53) pseudotyped HIV-1–Luciferase assay system the HIV Province of Truncatella replication China angustata a Tripeptide conjugates of chitosan (a natural marine byproduct), prepared in the laboratory.

Molecules 2019, 24, x FOR PEER REVIEW 25 of 40 MoleculesMolecules 201920192019,, , 24 2424,, , x xx FOR FORFOR PEER PEERPEER REVIEW REVIEWREVIEW 252525 ofofof 404040 anti-HIV-1; anti-HIV-1; neuroprotectanti-HIV-1;anti-HIV-1; neuroprotect neuroprotective effect on ive effect on neuroinflamiveive effecteffect onon Molecules 2019, 24, 3486 docosahexanoic neuroinflam 21 of 36 docosahexanoic not In vivo study on male rat models-Male F344 neuroinflammations docosahexanoicacid not In vivo study on male rat models-Male F344 mations [109] acid disclosednot InIn vivovivo studystudy(control) onon malemaleand HIV-1Tg ratrat models-Malemodels-Male rats F344F344 inducedmations by [109] (acidacid48) disclosed (control) and HIV-1Tg rats induced by [109][109] (48) disclosed (control)(control) andand HIV-1TgHIV-1Tg ratsrats ethanolinducedinduced (in byby ((4848)) ethanol (in Table 3. Cont. theethanolethanol presence (in(in the presence ofthethe HIV presencepresence viral of HIV viral Group Compound Location Organism Assay Dose Activityofofproteins) HIVHIV viralviral Structure Reference proteins)proteins) anti-HIV-1; anti-HIV-1anti-HIV-1;anti-HIV-1;anti-HIV-1;; Tutuila, EC50—In Vitro Model of HIV-1 Latency-high- reactivation Tutuila, Tutuila, EC50—InEC Vitro50—In Model Vitro of Model HIV-1 of HIV-1 Latency-high- reactivation radicicol radicicol Tutuila, H. EC5050—In Vitro Model of HIV-1 Latency-high- reactivationreactivationreactivation of latent American radicicolradicicolradicicolH. fuscoatra AmericanLatency-high-throughput H.H. throughput primary primary cell-based cell-based HIV-1 HIV-1 latency9.1 µM 9.1 µM of latent [110][110 ] (49) (49) AmericanAmerican fuscoatra throughputthroughputthroughput primary primaryprimary cell-based cell-basedcell-based HIV-1 HIV-1HIV-1 latency latencylatency 9.19.19.1 µM µMµMviral loadsofofof in latent latentlatent CD4 + [110][110][110] Samoa (((494949))) Samoa fuscoatrafuscoatrafuscoatra latency assay assay viral loads in SamoaSamoa assayassay T-cellsviralviral loadsloads inin Phlorotannin Samoa assay CD4+viral loadsT-cells in Phlorotannin CD4+ T-cells Phlorotannins and CD4+ T-cells Phlorotannins sss and andand anti-HIV-1; xanthones anti-HIV-1;anti-HIV-1;anti-HIV-1; and xanthones xanthonesxanthonesxanthones Tutuila, EC50—In Vitro Model of HIV-1 Latency-high- anti-HIV-1reactivation; Tutuila, pochonin B Tutuila, H.EC —InEC Vitro50—In Model Vitro of Model HIV-1 of HIV-1 Latency-high- reactivation pochonin B pochonin B AmericanTutuila, H. 50 throughputEC5050—In Vitro primary Model cell-based of HIV-1 HIV-1Latency-high- latency 39.6 µMreactivation reactivationreactivationof oflatent latent [110] American pochonin(50) H. B fuscoatra AmericanLatency-high-throughput fuscoatraH. throughput primary primary cell-based cell-based HIV-1 HIV-1 latency39.6 µM 39.6 µM of latent [110][110 ] (50) (50) AmericanSamoa fuscoatra throughputthroughput primaryprimaryassay cell-basedcell-based HIV-1HIV-1 latencylatency 39.639.6 µMµMviral loadsviralofof in loadslatentlatent CD4 + in [110][110] Samoa ((5050)) Samoa fuscoatrafuscoatra latency assay assay viral loads in SamoaSamoa assayassay T-cellsCD4+viralviral loads loadsT-cells inin CD4+CD4+ T-cellsT-cells

Auxiliary anti-HIV-1; AuxiliaryAuxiliary anti-HIV-1;anti-HIV-1;anti-HIV-1; Auxiliary therapy to Tutuila, EC50—In Vitro Model of HIV-1 Latency-high- reactivation therapy to Tutuila, EC50—In Vitro Model of HIV-1 Latency-high- anti-HIV-1reactivation; therapy to therapytherapyTutuila, toto pochonin C Tutuila, H.EC —InEC Vitro5050—In Model Vitro of Model HIV-1 of HIV-1 Latency-high- reactivationreactivation pochonin C HAART pochoninpochonin CC American H.H. 50 throughput primary cell-based HIV-1 latency 6.3 µMreactivation of oflatent latent [110] HAART HAARTHAARTAmerican (51) H. fuscoatraAmericanAmericanLatency-high-throughput fuscoatra throughputthroughputthroughput primary primary primaryprimary cell-based cell-based cell-basedcell-based HIV-1 HIV-1 HIV-1HIV-1 latency latencylatency6.3 µM 6.36.36.3 µM µMµM ofofof latent latentlatent [110][110][110][110 ] (51) therapy— (((515151))) Samoa fuscoatrafuscoatrafuscoatra assay viral loadsviral in loads CD4 +in therapy—ﬁsh therapy—therapy—Samoa SamoaSamoa latency assay assayassay viralviral loadsloads inin therapy—therapy—fish oil SamoaSamoa assayassay T-cellsCD4+viralviral loads loadsT-cells inin oil fishfishfish oil oiloil CD4+CD4+ T-cellsT-cells Yongxing sponge- YongxingYongxing sponge-sponge-sponge- anti-HIV-1; Island, associated anti-HIV-1;anti-HIV-1;anti-HIV-1; H Yongxing Island,truncateolsponge-associated O Island,Island, associatedassociated IC50—Anti-HIV bioassays-VSV-G inhibition of H truncateol O HainanIsland, associatedfungus IC50—Anti-HIV bioassays-VSV-G 39 µM inhibition of HH [111] truncateol O Hainan truncateoltruncateol fungusOO Hainan IC50—Anti-HIVfungus bioassays-VSV-GICIC5050—Anti-HIV pseudotyped bioassays-VSV-G 39 µManti-HIV-1 inhibitioninhibition; inhibition ofof OH [111] (52) Hainan fungusfungus pseudotyped HIV-1–Luciferase assay system39 µM 3939 µMµM the HIV OH [111][111][111 ] (52) Province of (((525252))) TruncatellaProvince of TruncatellaHIV-1–Luciferase pseudotypedpseudotyped assay HIV-1–LuciferaseHIV-1–Luciferase system assayassay systemsystem of the HIV replicationthethethe HIV HIVHIV H OH Province of Truncatella HO H Province of Truncatella replication HO O HH China angustata China angustata replicationreplicationreplication HOHO O Others ChinaChina angustataangustataangustata O Others OthersOthers Yongxing sponge- YongxingYongxing sponge-sponge-sponge- anti-HIV-1; Island, associated anti-HIV-1;anti-HIV-1;anti-HIV-1; Yongxing Island,truncateolsponge-associated P Island, associated IC50—Anti-HIV bioassays-VSV-G inhibition of truncateol P Island,Island, associatedassociated IC50—Anti-HIV bioassays-VSV-G inhibition of truncateol P Hainan truncateoltruncateol fungusPP Hainan IC —Anti-HIVfungus bioassays-VSV-GICIC5050—Anti-HIV pseudotyped bioassays-VSV-G 16.1 anti-HIV-1µM inhibitioninhibition; inhibition ofof [111] (53) HainanHainan 50 fungusfungusfungus pseudotyped HIV-1–Luciferase assay system16.1 µ M 16.116.116.1 µM µMµM the HIV [111][111][111][111 ] (53) Province of (((535353))) TruncatellaProvince of TruncatellaHIV-1–Luciferase pseudotypedpseudotyped assay HIV-1–LuciferaseHIV-1–Luciferase system assayassay systemsystem of the HIV replicationthethethe HIV HIVHIV ProvinceProvince ofof TruncatellaTruncatella replication China angustataProvinceChina of Truncatellaangustata replication China angustata replicationreplication a China angustataangustata a Tripeptide conjugates of chitosan (a natural marine byproduct), prepared in the laboratory. aa Tripeptide conjugates of chitosan (a natural marine byproduct), prepared in the laboratory. Tripeptide aconjugatesTripeptide of conjugates chitosan (a of natural chitosan marine (a natural byproduct), marine byproduct),prepared in preparedthe laboratory. in the laboratory.

Molecules 2019, 24, 3486x FOR PEER REVIEW 2622 of of 40 36

Marine sponges are not the sole source of bioactive proteins. For example, Jang et al. reported aboutMarine a new spongessmall hydroxyproline-rich are not the sole source peptide of bioactivefrom Alaska proteins. Pollack For collagen example, (APHCP, Jang et 21 al., Figure reported 8) thatabout exhibits a new small a unique hydroxyproline-rich antiviral activity peptide [94]. This from peptide Alaska Pollackis a Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro- collagen (APHCP, 21, Figure8) that Hyp-Glyexhibits a peptide, unique antiviral and the activityauthors [94 showed]. This peptidethat the ismost a Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly important part of a peptide for anti-HIV peptide,activity is and the the hydroxyl authors showedgroup at that hydroxyproline, the most important whereas part a of peptide a peptide with for only anti-HIV prolines activity does is not the exhibithydroxyl antiviral group atactivity. hydroxyproline, Its anti-HIV whereas 1 mode a of peptide action with is manifested only prolines through does the not inhibition exhibit antiviral of the inducedactivity. Itssyncytia anti-HIV formation 1 mode by of the action interference is manifested of an throughHIV fusion, the inhibition of cell the inducedlysis, RT syncytiaactivity, andformation the production by the interference of the p24 of antigen. an HIV fusion,It was shown inhibition that of APHCP cell lysis, can RT decrease activity, andthe HIV-1 the production induced of the p24 antigen. It was shown that APHCP can decrease the HIV-1 induced cell lysis at a potency cell lysis at a potency around EC50 of 459 µM (EC50 against anti-HIV-1 induced cell lysis—MTT assay). around EC of 459 µM (EC against anti-HIV-1 induced cell lysis—MTT assay). Additionally, through Additionally,50 through the 50inhibition of the viral RT at EC50 at 374 µM, this peptide’s crucial role in the inhibition of the viral RT at EC at 374 µM, this peptide’s crucial role in the inhibition of the the inhibition of the conversion of vira50 l RNA to DNA was also confirmed. With EC50 of 405 µM, this compoundconversion ofeffectively viral RNA suppressed to DNA was the also p24 conﬁrmed. production With in viral EC50 cells,of 405 asµ M,determined this compound by the e ﬀWesternectively blotsuppressed analysis. the p24 production in viral cells, as determined by the Western blot analysis.

Figure 8. StructureStructure of the Alaska Pollack collag collagenen hydroxyl proline (APCHP) peptide (21).

Similarly, one newnew anti-HIVanti-HIV peptide was isolated from SpirulinaSpirulina maxima (SM-peptide)(SM-peptide) [[95]–the95]–the Leu-Asp-Ala-Val-Asn-Arg peptide,peptide, andand thethe authors showed its HIV-1 infection inhibition in a human T cell line MT4. The The peptide peptide inhibited inhibited cell cell lysis, lysis, p24 p24 antigen antigen production, production, and and HIV-1 HIV-1 RT. RT. Specifically, Speciﬁcally, IC50 (obtained(obtained by by a a cell cell viability viability assay) assay) against against an an anti-HIV anti-HIV 1 1 infection infection was was determined determined as as 0.691 0.691 mM, mM, the inhibition of the HIV-1-induced RT activation (R (RTT assay kit) in MT4 cells was at a high 90% at a concentration of 1.093 mM, and the p24 production (p24 antigen production assay) was inhibited at 95% at a concentration of 1.093 mM.

2.5. Alkaloids 2.5. Alkaloids Marine organisms organisms are are well-established well-established sources sources of natural of natural alkaloids. alkaloids. Although Although the term ‘alkaloid’ the term ‘alkaloid’seems puzzling seems and puzzling is prone and to isscientific prone to controversy, scientiﬁc controversy, alkaloids are alkaloids generally are defined generally as nitrogen- deﬁned containingas nitrogen-containing compoundscompounds derived from derived plants from and plants animals. and Relatively animals. Relatively few alkaloids few alkaloids from marine from sourcesmarine sourceshave been have found been foundto possess to possess antiretroviral antiretroviral properties properties and, and, so sofar, far, none none have have found found their clinical use. Aspernigrin CC ( 22(22, Figure, Figure9) and9) and malformin malformin C ( 23, C (Figure23, Figure9) have 9) beenhave isolated been isolated from marine-derived from marine- derivedblack aspergili, black aspergili,Aspergillus Aspergillus niger SCSIO niger Jcw6F30, SCSIO andJcw6F30, their inhibitoryand their activityinhibitory against activity the against chemokine the chemokinereceptor subtype receptor 5 (CCR5) subtype tropic 5 (CCR5) HIV-1 tropic SF162 HIV- has been1 SF162 evaluated. has been They evaluated. show potent They show inhibition potent of infection with IC50 values 4.7 0.4 µM and 1.4 0.06 µM, which is comparable to the nucleoside reverse inhibition of infection with IC± 50 values 4.7 ± 0.4± µM and 1.4 ± 0.06 µM, which is comparable to the transcriptase inhibitor—abacavir (IC50 = 0.8 0.1 µM) and the HIV-1 entry inhibitor ADS-J1 (IC50 = 0.8 nucleoside reverse transcriptase inhibitor—abacavir± (IC50 = 0.8 ± 0.1 µM) and the HIV-1 entry inhibitor± 0.1 µM). In comparison to other aspernigrins, it has been suggested that the 2-methylsuccinic moiety is ADS-J1 (IC50 = 0.8 ± 0.1 µM). In comparison to other aspernigrins, it has been suggested that the 2- methylsuccinicresponsible for themoiety potency is responsible of aspernigrin for the C [potency96]. of aspernigrin C [96].

Molecules 20192019,, 2424,, 3486x FOR PEER REVIEW 2723 of of 3640 Molecules 2019, 24, x FOR PEER REVIEW 27 of 40 Molecules 2019, 24, x FOR PEER REVIEW 27 of 40

Figure 9. Structures of aspernigrin C (22) and malformin C (23). FigureFigure 9. 9. Structures Structures ofof aspernigrin C C ( (2222)) and andand malformin malforminmalformin C CC(23 ((23). ).). Thiodiketopiperazine-type alkaloids, eutypellazines A-M, isolated from the EtOAc extract of the fermentationThiodiketopiperazine-typeThiodiketopiperazine-type broth of deep-sea sediment alkaloids,alkaloids, alkaloids, fungus eutypellazineseutypellazines Eutypella A-M, A-M,A-M, sp. shows isolated isolatedisolated potent from fromfrom theinhibitory thethe EtOAc EtOAcEtOAc extract effects extractextract of against oftheof the fermentationfermentationpNL4.3.Env-.Lucfermentation brothbroth broth co-transfected ofof of deep-seadeep-sea deep-sea sedimentsediment sediment293T HIV fungusfungus model Eutypella Eutypellacells. Eutypellazine sp spsp. ..shows shows potent potent E (24 inhibitory, inhibitoryFigure 10) effects eeffectsexertsﬀects against activity against pNL4.3.Env-.Luc co-transfected 293T HIV model cells. Eutypellazine E (24, Figure 10) exerts activity in inpNL4.3.Env-.Luc pNL4.3.Env-.Luca low micromolar co-transfected co-transfected range (IC 293T 50293T = 3.2 HIVHIV ± model0.4 µM), cells.cells. while Eutypellazine Eutypellazine eutypellazine E E (24 (24 , JFigure, Figure(25, Figure10) 10) exerts exerts 10) activity shows activity a ain low a low micromolar micromolar range range (IC50 =(IC3.25050 = 0.43.2µ ±M), 0.4 while µM), eutypellazine while eutypellazine J (25, Figure J ( 2510,) showsFigure a10) reactivating shows a reactivatingin a low micromolar effect toward range latent (IC HIV-1± = 3.2 in ± J-Lat0.4 µM), A2 cells.while This eutypellazine could be used J (25 as, Figure a promising 10) shows strategy a etoreactivatingﬀ reactivatingectexpunge toward theeffectlatent effect HIV-1 toward HIV-1toward infection inlatent latent J-Lat HIV-1byHIV-1 A2 activating cells. in J-Lat This latentA2 couldA2 cells.cells. bevirus This usedThis cellular could ascould apromising be bereservoirs used used as as strategya promisingina promising combination to expunge strategy strategy with the HIV-1HAARTto toexpunge expunge infection [97]. the the byHIV-1 HIV-1 activating infection infection latent byby virus activatingactivating cellular latentlatent reservoirs virusvirus cellular incellular combination reservoirs reservoirs with in in combination HAART combination [97]. with with HAARTHAART [97]. [97].

FigureFigure 10. 10. Structures Structures ofof eutypellazine E E ( (2424)) )and and eutypellazine eutypellazineeutypellazine J ( JJ25 ((2525). ).). Figure 10. Structures of eutypellazine E (24) and eutypellazine J (25). TheThe S. S. cartericarteri carteri Red RedRed SeaSeaSea spongespongesponge extractextractextract yieldsyields three threethree previously previouslypreviously characterized characterizedcharacterized compounds: compounds: debromohymenialdisinedebromohymenialdisineThe S. carteri Red (DBH) (DBH)Sea(DBH) sponge ( (26 2626,, , FigureFigure Figure extract 11), 11 ),yieldshymenialdisine hymenialdisine three previously (HD) (HD) (HD) (27 (27, (Figure,27 characterizedFigure, Figure 11), 11), and 11 and), oroidincompounds: and oroidin oroidin (28 (, 28, (Figuredebromohymenialdisine28Figure, Figure 11). 11). 11DBH ).DBH DBH and and and HD HD (DBH) HD exhibitedexhibited exhibited (26, Figure aa 30–40% a 30–40% 11), inhibitionhymenialdisine inhibition ofof HIV-1 ofHIV-1 HIV-1(HD) at at (3.1 at273.1, 3.1 µMFigure µMµ Mand and and11), 13 13 13andµM µMµ Moroidinbut but with withwith ( 28, associatedFigureassociated 11). cytotoxicity.DBH cytotoxicity. and HD Conversely, Conversely, exhibited oroidinoroidina 30–40% displayed inhibition a a 50% 50% of inhibition HIV-1 inhibition at of3.1 of viral viralµM replication and replication 13 µM at at50but 50µM with µµM M withoutwithoutassociatedwithout observedobserved observed cytotoxicity. cytotoxicity.cytotoxicity. cytotoxicity. Conversely, Also,Also, Also, oroidin itit showedshowed displayed inhibition a of50% of HIV-1 HIV-1 inhibition reverse reversereverse of transcriptase transcriptasetranscriptaseviral replication up upup to to90%toat 90%50 at µM at 25without25 µµMcMc µMc [[98].observed98 [98].]. cytotoxicity. Also, it showed inhibition of HIV-1 reverse transcriptase up to 90% at 25 µMc [98].

FigureFigure 11. 11.Structures Structures of of debromohymenialdisine debromohymenialdisine ( (2626),), 10Z-hymenialdisine 10Z-hymenialdisine (27 (27), ),and and oroidin oroidin (28 ().28 ).

Figure 11. Structures of debromohymenialdisine (26), 10Z-hymenialdisine (27), and oroidin (28). Figure 11. Structures of debromohymenialdisine (26), 10Z-hymenialdisine (27), and oroidin (28).

Molecules 2019, 24, 3486 24 of 36 Molecules 2019, 24, x FOR PEER REVIEW 28 of 40 The two known alkaloids of the aaptamine family containing 1H-benz[de]-1,6-naphthyridine The two known alkaloids of the aaptamine family containing 1H-benz[de]-1,6-naphthyridine skeleton, namely 3-(phenetylamino)demethyl(oxy)aaptamine (29, Figure 12) and skeleton, namely 3-(phenetylamino)demethyl(oxy)aaptamine (29, Figure 12) and 3- 3-(isopentylamino)demethyl(oxy)aaptamine (30, Figure 11), were isolated from the sponge A. (isopentylamino)demethyl(oxy)aaptamine (30, Figure 11), were isolated from the sponge A. aptos. aptos. They exhibited anti-HIV activity, with inhibitory rates of 88.0% and 72.3%, respectively, at a They exhibited anti-HIV activity, with inhibitory rates of 88.0% and 72.3%, respectively, at a concentration of 10 µM[99]. concentration of 10 µM [99].

Figure 12.12. StructuresStructures of of3-(phenetylamino)dimethyl(oxo)aaptamine 3-(phenetylamino)dimethyl(oxo)aaptamine (29) (29and) and3- (isopentylamino)dimethyl3-(isopentylamino)dimethyl (oxo)aaptamine (oxo)aaptamine (30 (30). ).

Bengamide A ( 31, Figure 1313),), haliclonycyclaminehaliclonycyclamine A+B A+B( (3232,, Figure Figure 13)13) and and keramamine keramamine C C ( (3333,, µ Figure 1313)) inhibit HIV-1 withwith a 50% eeffectiveﬀective concentrationconcentration ofof 3.83.8 µMM oror less.less. The most potent among them, bengamide A, blocked HIV-1 in a T cell line with an EC of 0.015 µM (which was comparable them, bengamide A, blocked HIV-1 in a T cell line with an EC5050 of 0.015 µM (which was comparable µ µ µ to control control antiretrovirals antiretrovirals indinavir indinavir 0.029 0.029 µM,M, efavirenz efavirenz 0.0024 0.0024 µM,M, and and raltegravir raltegravir 0.011 0.011 µM)M) and and in in peripheral blood mononuclear cells with EC of 0.032 µM. It was concluded that HIV-1 LTR peripheral blood mononuclear cells with EC50 of 500.032 µM. It was concluded that HIV-1 LTR NF-κB κ responseNF- B response elements elements are required are required for a for bengamide a bengamide A-mediated A-mediated inhibition inhibition of of LTR-dependent LTR-dependent gene expression [[100].100].

OH OMe O H N N NH OH OH O O 31 O (CH2)12Me

H NH H N N H H N H H N

32 33 32 33 Figure 13. Structures of bengamide A (31),), haliclonacyclamineshaliclonacyclamines AA + BB( (32),), keramamine keramamine C ( 33).

Phenylspirodrimane, stachybotrin D D ( 34,, Figure 14)14) isolated from the sponge-derivedsponge-derived fungus Stachybotrys chartarumchartarumMXH-X73, MXH-X73, was was discovered discovered to be to a HIV-1be a RTHIV-1inhibitor, RT inhibitor, which showed which inhibitory showed µ inhibitoryeﬀects on the effects wild on type the (EC wild50 8.4 typeM) (EC and50 8.4 ﬁve µM) NNRTI-resistant and five NNRTI-resistant HIV-1 strains (ECHIV-150 7.0; strains 23.8; (EC 13.3;50 14.2;7.0; 23.8;6.2 µ M)13.3; [101 14.2;]. 6.2 µM) [101].

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Figure 14. Structure of stachybotrin D (34 ). Figure 14. StructureStructure of stachybotrin D ( 34). 2.6. Diterpenes 2.6. Diterpenes 2.6. DiterpenesMany terpenes from marine natural products demonstrated anti-HIV properties. Mechanisms of actionMany involve terpenes blocking fromfrom marinemarine of different naturalnatural steps products products of the demonstrated demonstratedHIV-1 replicative anti-HIV anti-HIV cycle properties. properties.as reverse Mechanisms transcriptaseMechanisms of ofinhibitors,action action involve involve protease blocking blocking inhibitors, of di offferent di orfferent stepsentry ofsteps inhibitors. the HIV-1of the Among replicativeHIV-1 replicativethem, cycle di asterpenes reversecycle as transcriptasefrom reverse marine transcriptase inhibitors,algae are inhibitors,proteasenowadays inhibitors, proteasein the spotlight or inhibitors, entry inhibitors.due or to entrytheir Among inhibitors.promising them, Amonganti-HIV diterpenes them, activities from di marineterpenes [102]. algae Dolabellanefrom are marine nowadays diterpenes algae in are the nowadaysarespotlight compounds due in tothe theirfrom spotlight promisingthe diterpene due anti-HIVto their group promising activities that have [102anti-HIV recently]. Dolabellane activitiesbeen extensivel diterpenes [102]. yDolabellane studied are compounds for diterpenes their fromanti- areHIVthe diterpenecompounds activity. groupPardo-Vargas from that the have diterpene et recently al. characterized group been extensivelythat have three recently studiednew dolabellane been for their extensivel anti-HIV diterpenesy studied activity. isolated for Pardo-Vargas their from anti- the HIVmarineet al. activity. characterized brown Pardo-Vargas alga three Dictyota new et dolabellane al.pfaffii characterized from diterpenes Northeast three isolated new Brazil: dolabellane from (1R*,2E,4R*,7S,10S*,11S*,12R*)10,18- the marine diterpenes brown algaisolatedDictyota from pfa theffii marinediacetoxy-7-hydroxy-2,8(17)-dolabelladiene,from Northeast brown Brazil:alga (1R*,2E,4R*,7S,10S*,11S*,12R*)10,18-diacetoxy-7-hydroxy-2,8(17)-dolabelladiene,Dictyota pfaffii from Northeast(1R* ,2E,4R*,7R*,10S*,11S*,12R*)10,18-diacetoxy-7-Brazil: (1R*,2E,4R*,7S,10S*,11S*,12R*)10,18- diacetoxy-7-hydroxy-2,8(17)-dolabelladiene,(1R*,2E,4R*,7R*,10S*,11S*,12R*)10,18-diacetoxy-7-hydroxy-2,8(17)-dolabelladiene,hydroxy-2,8(17)-dolabelladiene, (1R*,2E,4R*,8E,10S*,11S,12R*)10,18-diacetoxy-7-hydroxy-2,8- (1R*,2E,4R*,7R*,10S*,11S*,12R*)10,18-diacetoxy-7- hydroxy-2,8(17)-dolabelladiene,(1R*,2E,4R*,8E,10S*,11S,12R*)10,18-diacetoxy-7-hydroxy-2,8-dolabelladiene,dolabelladiene, named dolabelladienols (1R*,2E,4R*,8E,10S*,11S,12R*)10,18-diacetoxy-7-hydroxy-2,8- A–C (35–37, Figure 15), respectively named [102]. In dolabelladienols particular, the dolabelladiene,A–Cnew (compounds,35–37, Figure named dolabelladienols15), dolabelladienols respectively [102A and].A–C In particular,B,(35 –showed37, Figure the potent new 15), compounds,respectivelyanti-HIV-1 dolabelladienols[102].activities In particular, that can A and thebe newconfirmedB, showed compounds, with potent their anti-HIV-1dolabelladienols low IC50 activities values A of thatand 2.9 can B,and showed be 4.1 confirmed µM potent and withlow anti-HIV-1 theircytotoxic low activities ICactivity50 values againstthat of 2.9can MT-2and be lymphocyte4.1 µM and lowtumor cytotoxic cells. These activity promising againstMT-2 anti-HIV-1 lymphocyte agents tumor were even cells. more These active promising than previously anti-HIV-1 confirmed with their low IC50 values of 2.9 and 4.1 µM and low cytotoxic activity against MT-2 lymphocyteknownagents were2,6-dolabelladienes tumor even more cells. active These series. than promising previously anti-HIV-1 known agents 2,6-dolabelladienes were even more series. active than previously known 2,6-dolabelladienes series.

Figure 15. StructuresStructures of the new dolabellane diterpenoids dolabelladienols A–C (35–37). Figure 15. Structures of the new dolabellane diterpenoids dolabelladienols A–C (35–37). De Souza Barros et al. tested marine dolastanes ( 38, 40, Figure 16)16) and secodolastane diterpenes (39, Figure 16) isolated from the brown alga Canistrocarpus cervicornis for anti-HIV-1 activity [103]. They (39, FigureDe Souza 16) Barrosisolated et fromal. tested the brownmarine algadolastanes Canistrocarpus (38, 40, Figurecervicornis 16) andfor anti-HIV-1secodolastane activity diterpenes [103]. observed that the marine diterpenes 38–40 inhibit the HIV-1 replication in a dose-dependent manner (They39, Figure observed 16) isolatedthat the frommarine the diterpenes brown alga 38 –Canistrocarpus40 inhibit the cervicornisHIV-1 replication for anti-HIV-1 in a dose-dependent activity [103]. (EC values of 0.35, 3.67, and 0.794 µM) without a cytotoxic effect (CC values ranging from 935 to Theymanner50 observed (EC50 values that the of 0.35,marine 3.67, diterpenes and 0.794 38µM)–40 without inhibit athe cytotoxic HIV-1 replicationeffect50 (CC50 in values a dose-dependent ranging from 1910935 toµ M).1910 Additionally, µM). Additionally, they investigated they investigated the virucidal the evirucidalffect of these effect diterpenes of these and diterpenes their potential and their use manner (EC50 values of 0.35, 3.67, and 0.794 µM) without a cytotoxic effect (CC50 values ranging from as microbicides. Dolastane-diterpenes 38 and 40 showed a potent effect on HIV-1 infectivity, whereas 935potential to 1910 use µM). as microbicidAdditionally,es. Dolastane-diterpenesthey investigated the 38virucidal and 40 effect showed of these a potent diterpenes effect onand HIV-1 their no virucidal effect was observed for secodolastane diterpene 39, demonstrating another mechanism of potentialinfectivity, use whereas as microbicid no virucidales. Dolastane-diterpenes effect was observed for38 secodolastaneand 40 showed diterpene a potent 39 effect, demonstrating on HIV-1 antiretroviral activity. Therefore, the authors suggested a potential use of marine dolastanes 38 and 40 infectivity,another mechanism whereas noof virucidalantiretroviral effect activity. was observed Therefore, for secodolastane the authors suggested diterpene 39a potential, demonstrating use of as microbicides that could directly inhibit virus infectivity and possibly act before the virus penetrates anothermarine dolastanesmechanism 38 of and antiretroviral 40 as microbicides activity. that Therefore, could directly the authors inhibit suggestedvirus infectivity a potential and possibly use of the target cells [103]. marineact before dolastanes the virus 38 penetrates and 40 as the microbicides target cells that [103]. could directly inhibit virus infectivity and possibly act before the virus penetrates the target cells [103].

Molecules 2019, 24, 3486 26 of 36 MoleculesMolecules 20192019,, 2424,, xx FORFOR PEERPEER REVIEWREVIEW 3030 ofof 4040

FigureFigure 16.16. StructuresStructuresStructures ofof marimari marinenene dolastanesdolastanes (( 3838 andand 4040))) andand and secodolastanesecodolastane secodolastane diterpenediterpene diterpene (( 3939)) derivedderived derived fromfrom CanistrocarpusCanistrocarpus cervicornis cervicornis..

DolabelladienetriolDolabelladienetriol fromfrom from brownbrown brown algaalga DictyotaDictyota sppspp hashas alsoalso beenbeen evaluatedevaluated asas aa potential potential microbicidemicrobicide againstagainst against HIV-1HIV-1 HIV-1 inin in tissuetissue tissue explants.explants. explants. Namely,Namely, Namely, StephensStephens Stephens etet al.al. etexaminedexamined al. examined thethe 8,10,18-8,10,18- the trihydroxy-2,6-dolabelladienetrihydroxy-2,6-dolabelladiene8,10,18-trihydroxy-2,6-dolabelladiene ((4141,, FigureFigure (41, 17) Figure17) inin pretreated17pretreated) in pretreated peripheralperipheral peripheral bloodblood bloodcellscells (PBMC) cells(PBMC) (PBMC) andand macrophagesmacrophagesand macrophages alongalong along withwith their withtheir protective theirprotective protective effecteffect eininﬀ ectthethe in exex the vivovivo ex explantexplant vivo explant modelmodel modelofof thethe uterine ofuterine the uterine cervixcervix [104].[104].cervix Pre-treatment [Pre-treatment104]. Pre-treatment ofof peripheralperipheral of peripheral PBMCPBMC PBMC andand and macrophagesmacrophages macrophages withwith with dolabelladienotrioldolabelladienotriol dolabelladienotriol showed showed inhibitoryinhibitory eeffectseffectsﬀects on onon HIV-1 HIV-1HIV-1 replication. replication.replication. Furthermore, Furthermore,Furthermore, in the inin explant thethe explantexplant model dolabelladienetriolmodelmodel dolabelladienetrioldolabelladienetriol inhibited inhibitedinhibitedviral replication viralviral replicationreplication in a dose-dependent inin aa dodose-dependentse-dependent manner from mannermanner 20 to fromfrom 99% 2020 in toto concentrations 99%99% inin concentrationsconcentrations of 0.15 and ofof 0.150.15 14.4 andandµM 14.4without14.4 µMµM without awithout loss in aa the lossloss viability inin thethe viabilityviability of the tissue. ofof thethe tissue. Thetissue. authors TheThe authorsauthors concluded concludedconcluded that this thatthat compound thisthis compoundcompound has great hashas greatpotentialgreat potentialpotential as a as possibleas aa possiblepossible microbicide. microbicide.microbicide. The TheThe same samesame compound compoundcompound was waswas also alsoalso theoretically theoreticallytheoretically analyzed analyzedanalyzed as as anan inhibitorinhibitor ofofof thethethe wild-type wild-typewild-type and andand mutants’ mutants’mutants’ HIV-1 HIV-1HIV-1 reverse revereve transcriptaserserse transcriptasetranscriptase [105 ]. [105].[105]. Firstly, Firstly,Firstly, the structure-activity thethe structure-structure- activityactivityrelationship relationshiprelationship studies revealedstudiesstudies revealedrevealed that a low thatthat dipole aa lowlow moment dipoledipole andmomentmoment high and HOMOand highhigh (highest HOMOHOMO occupied (highest(highest molecularoccupiedoccupied molecularmolecularorbital)-LUMO orbital)-LUMOorbital)-LUMO (lowest unoccupied (lowest(lowest unoccupiedunoccupied molecular orbital) molemolecularcular gap valuesorbital)orbital) are gapgap related valuesvalues to the areare antiviral relatedrelated activity.toto thethe antiviralantiviralSecondly, activity.activity. molecular Secondly,Secondly, docking molecularmolecular studies dockingdocking with RT stst wild-typeudiesudies withwith and RTRT wild-typewild-type mutants showed andand mutantsmutants a seahorse-like showedshowed aa seahorse-likeseahorse-likeconformation conformationconformation of 8,10,18-trihydroxy-2,6-dolabelladiene, ofof 8,8,10,18-trihydroxy-2,6-dolabelladiene,10,18-trihydroxy-2,6-dolabelladiene, hydrophobic interactions, hydrophobichydrophobic and interactions,interactions, hydrogen bonds andand hydrogenwithhydrogen important bondsbonds residues withwith importantimportant of the binding residuesresidues pocket. ofof thethe bibi Finally,ndingnding pocket.pocket. the authors Finally,Finally, suggested thethe authorsauthors a new suggestedsuggested derivative aa newnew of derivativederivativethe 8,10,18-trihydroxy-2,6-dolabelladiene ofof thethe 8,10,18-trihydroxy-2,6-dolabelladiene8,10,18-trihydroxy-2,6-dolabelladiene with an aromatic withwith moiety anan aromaticaromatic in the moiety doublemoiety in bondin thethe to doubledouble improve bondbond its totobiological improveimprove activity. itsits biologicalbiological activity.activity.

FigureFigure 17.17. StructureStructureStructure ofof of (1(1 (1RR,2,2,2EE,4,4,4RR,6,6,6EE,8,8,8SS,10,10,10SS,11,11,11SS,12,12,12RR)-8,10,18-trihydroxy-2,6-dolabelladiene)-8,10,18-trihydroxy-2,6-dolabelladiene)-8,10,18-trihydroxy-2,6-dolabelladiene ( (4141).).

AlthoughAlthough dolabellanedolabellanedolabellane diterpenes diterpenesditerpenes of ofof brown brownbrown alga algaalgaDictyota DictyotaDictyotaspp showedsppspp showedshowed a strong aa strong anti-HIV-1strong anti-HIV-1anti-HIV-1 activity, activity,activity,this was thisthis not was conﬁrmedwas notnot confirmedconfirmed for dolabellane forfor dolabellanedolabellane diterpenes ditedite isolatedrpenesrpenes fromisolatedisolated octocorals. fromfrom octocorals.octocorals. Therefore, Therefore,Therefore, some chemical somesome chemicalchemicaltransformations transformationstransformations have been havehave conducted beenbeen conductedconducted to improve toto the improveimprove anti-HIV-1 thethe anti-HIV-1anti-HIV-1 potency of potency thepotency main ofof dolabellane thethe mainmain dolabellane13-keto-1(dolabellaneR ),11(13-keto-1(13-keto-1(S)-dolabella-3(RR),11(),11(SS)-dolabella-3()-dolabella-3(E),7(E),12(18)-trieneEE),7(),7(EE),12(18)-triene),12(18)-triene from Caribbean fromfrom octocoral CaribbeanCaribbeanEunicea octocoraloctocoral laciniata EuniceaEunicea[106]. laciniatalaciniataOxygenated [106].[106]. dolabellanes OxygenatedOxygenated derivatives dolabellanesdolabellanes (42 –derivativesderivatives44, Figure 18 ((4242),– obtained–4444,, FigureFigure by 18), epoxidation,18), obtainedobtained epoxide byby epoxidation,epoxidation, opening, epoxideepoxideand allylic opening,opening, oxidation andand of ketodolbellatrieneallylicallylic oxidationoxidation ofof have ketodoketodo shownlbellatrienelbellatriene signiﬁcantly havehave improved shownshown significantly antiviralsignificantly activities improvedimproved and a antiviralantivirallow cytotoxicity activitiesactivities to and MT-2and aa cells, lowlow whichcytotoxicitycytotoxicity makes toto them MT-2MT-2 promising cells,cells, whichwhich antiviral makesmakes compounds. themthem promisingpromising antiviralantiviral compounds.compounds.

Molecules 2019, 24, x FOR PEER REVIEW 30 of 40

Figure 16. Structures of marine dolastanes (38 and 40) and secodolastane diterpene (39) derived from Canistrocarpus cervicornis.

Dolabelladienetriol from brown alga Dictyota spp has also been evaluated as a potential microbicide against HIV-1 in tissue explants. Namely, Stephens et al. examined the 8,10,18- trihydroxy-2,6-dolabelladiene (41, Figure 17) in pretreated peripheral blood cells (PBMC) and macrophages along with their protective effect in the ex vivo explant model of the uterine cervix [104]. Pre-treatment of peripheral PBMC and macrophages with dolabelladienotriol showed inhibitory effects on HIV-1 replication. Furthermore, in the explant model dolabelladienetriol inhibited viral replication in a dose-dependent manner from 20 to 99% in concentrations of 0.15 and 14.4 µM without a loss in the viability of the tissue. The authors concluded that this compound has great potential as a possible microbicide. The same compound was also theoretically analyzed as an inhibitor of the wild-type and mutants’ HIV-1 reverse transcriptase [105]. Firstly, the structure- activity relationship studies revealed that a low dipole moment and high HOMO (highest occupied molecular orbital)-LUMO (lowest unoccupied molecular orbital) gap values are related to the antiviral activity. Secondly, molecular docking studies with RT wild-type and mutants showed a seahorse-like conformation of 8,10,18-trihydroxy-2,6-dolabelladiene, hydrophobic interactions, and hydrogen bonds with important residues of the binding pocket. Finally, the authors suggested a new derivative of the 8,10,18-trihydroxy-2,6-dolabelladiene with an aromatic moiety in the double bond to improve its biological activity.

Figure 17. Structure of (1R,2E,4R,6E,8S,10S,11S,12R)-8,10,18-trihydroxy-2,6-dolabelladiene (41).

Although dolabellane diterpenes of brown alga Dictyota spp showed a strong anti-HIV-1 activity, this was not confirmed for dolabellane diterpenes isolated from octocorals. Therefore, some chemical transformations have been conducted to improve the anti-HIV-1 potency of the main dolabellane 13-keto-1(R),11(S)-dolabella-3(E),7(E),12(18)-triene from Caribbean octocoral Eunicea laciniata [106]. Oxygenated dolabellanes derivatives (42–44, Figure 18), obtained by epoxidation, epoxide opening, and allylic oxidation of ketodolbellatriene have shown significantly improved antiviralMolecules 2019 activities, 24, 3486 and a low cytotoxicity to MT-2 cells, which makes them promising antiviral27 of 36 compounds.

Molecules 2019, 24, x FOR PEER REVIEW 31 of 40

FigureFigure 18. Structures ofof semi-synthesizedsemi-synthesized oxygenated oxygenated dolabellanes dolabellanes (42 (42–44–44) originally) originally isolated isolated from from the theCaribbean Caribbean octocoral octocoralEunicea Eunicea laciniata laciniata. .

2.7.2.7. Phlorotannins Phlorotannins and and Xanthones Xanthones PhlorotanninsPhlorotannins are are tannin tannin derivatives derivatives made made from from several phloroglucinol units units linked linked to to each otherother in different different ways. Phlorota Phlorotanninsnnins contain contain phenyl phenyl linkage linkage (fuc (fucols),ols), ether ether linkage (fuhalols and phlorethols), phenylphenyl and and ether ether linkage linkage (fucophloroethols), (fucophloroethols), and dibenzodioxinand dibenzodioxin linkage linkage (eckols) (eckols) [86,107]. [86,107].So far, a So series far, ofa phlorotanninsseries of phlorotannins have been have identified been identified with potent with anti-HIV potent activity.anti-HIV Foractivity. example, For example,8,80-bieckol 8,8′ and-bieckol 6,60-bieckol and 6,6′-bieckol from marine from brownmarine algabrownEcklonia alga Ecklonia cava has cava shown has shown an enhanced an enhanced HIV-1 HIV-1inhibitory inhibitory effect effect [112,113 [112,113].]. Karadeniz Karadeniz et al. et reportedal. reported that that 8,4 8,4000-dieckol′′′-dieckol ( 45(45,, Figure Figure 1919)) isis another phlorotannin derivative derivative isolated isolated fr fromom the the same same brown brown alga alga that that coul couldd be be used as as a drug candidate forfor the development of new generation anti-HIV therapeutic agents [[107].107]. The The compound showed HIV-1HIV-1 inhibitory activity at noncytotoxic concentr concentrations.ations. More More precisely, precisely, the the results indicated that 8,48,4′′′000-dieckol-dieckol inhibited inhibited the the cytopathic cytopathic effects effects of of HIV-1, HIV-1, including including HIV-1 HIV-1 induced induced syncytia syncytia formation, formation, lyticlytic effects, effects, and viral p24 antigenantigen production.production. Furthermore, 8,4000′′′-dieckol-dieckol inhibited inhibited an an HIV-1 HIV-1 entry entry andand RT enzyme with the inhibition ratio of 91% at a concentration of 50 µµM.M.

Figure 19. Chemical structure of 8,4000′′′-dieckol-dieckol ( (4545)) from from E.E. cava cava. .

Recently,Recently, for the first first time, xanthone dimer dimer was was identified identified as as a a potential potential anti-HIV-1 anti-HIV-1 agent agent [108]. [108]. Xanthones areare secondary secondary metabolites metabolites from from higher higher plant plant families, famili fungi,es, andfungi, lichen and [114 lichen,115]. [114,115]. Although Althoughstructurally structurally related to related flavonoids, to flavonoids, xanthones xanthones are not are as not frequently as frequently encountered encountered in nature in nature [9]. [9].Penicillixanthone Penicillixanthone A (PXA)A (PXA) (46 (,46 Figure, Figure 20 20),), a a natural natural xanthone xanthone dimer, dimer, has has beenbeen isolatedisolated from the the jellyfish-derivedjellyfish-derived fungusfungusAspergillus Aspergillus fumigates fumigateswith with fourteen fourteen other other natural natural products products [108 [108].]. However, However, only onlypenicillixanthone penicillixanthone A showed A showed inhibitory inhibitory activities activi in anties HIV in infection.an HIV infection. Marine-derived Marine-derived PXA displayed PXA displayedpotent anti-HIV-1 potent anti-HIV-1 activity against activity CCR5-tropic against CCR5-tropic HIV-1 SF162 HIV-1 and CXCR4-tropicSF162 and CXCR4-tropic HIV-1 NL4-3, HIV-1 with NL4-3,IC50 of with 0.36 andIC50 0.26of 0.36µM, and respectively. 0.26 µM, respectively. A molecular A docking molecular study docking confirmed studythat confirmed PXA might that PXA bind might bind to either CCR5 or CXCR4 to prevent HIV entry into target cells. Therefore, PXA, as a CCR5/CXCR4 dual-coreceptor antagonist, may be seen as a new potential lead product type for the development of anti-HIV therapeutics.

Molecules 2019, 24, 3486 28 of 36

to either CCR5 or CXCR4 to prevent HIV entry into target cells. Therefore, PXA, as a CCR5/CXCR4 dual-coreceptor antagonist, may be seen as a new potential lead product type for the development of Molecules 2019, 24, x FOR PEER REVIEW 32 of 40 anti-HIVMolecules 2019 therapeutics., 24, x FOR PEER REVIEW 32 of 40

Figure 20. Structure of penicillixanthone A (46). Figure 20. Structure of penicillixanthone A (46).

2.8.2.8. FishFish OilOil asas anan AdjuvantAdjuvant toto HAARTHAART Therapy Therapy HAARTHAART therapy therapy can can causecause severesevere sideside effects,effects, effects, e.e. e.g.,g.,g., insulininsulin insulin resistance,resistance, resistance, lipoatrophy,lipoatrophy, lipoatrophy, dyslipidemia,dyslipidemia, andand abnormalities abnormalities of of fat fat distribution. distribution. Therefore,Therefore, findingfinding finding an an adequate adequate diet diet and and supplementation supplementation to to lowerlower the thethe negative negativenegative effects eeffectsffects of of thethe HAARTHAART combinationcombinatiocombinationn therapytherapy isis desirabledesirable [[116116].116].]. Fish Fish oil oil containscontains omega-3omega-3 polyunsaturated polyunsaturated fattyfatty acidsacids (PUF(PUF (PUFA),A),A), eicosapentaenoic eicosapentaenoic (EPA,(EPA, 20:5n-3) 20:5n-3) ( (4747,, Figure Figure 21)2121)) and andand docosahexaenoicdocosahexaenoic (DHA,(DHA,(DHA, 22:6n-3) 22:6n-3)22:6n-3) (48 ((4848, Figure,, FigureFigure 21 ) 21)21) acids, acids,acids, which whichwhich may may havemay have beneficialhave beneficialbeneficial effects effects foreffects HIV-infected forfor HIV-HIV- infectedpatients.infected patients.patients. It has been ItIt hashas shown beenbeen that shownshown the addition thatthat thethe additionaddition of fish oil ofof to fishfish the oiloil diet toto of thethe HIV-infected dietdiet ofof HIV-infectedHIV-infected individuals individualsindividuals receiving receivingusualreceiving antiretroviral usualusual antiretroviralantiretroviral therapy can therapytherapy significantly cancan significsignific lowerantlyantly serum lowerlower triglycerides serumserum triglyceridestriglycerides levels [117 levelslevels], which [117],[117], is which highlywhich isrelevantis highlyhighly knowing relevantrelevant thatknowingknowing HIV dyslipidemiathatthat HIVHIV dyslipidemiadyslipidemia is a serious isis problem aa seriousserious related problemproblem to an relatedrelated increased toto anan frequency increasedincreased of frequencycardiovascularfrequency ofof cardiovascularcardiovascular disease. disease.disease.

Figure 21. Structures of eicosapentanoic (47) and docosahexanoic acid (48). Figure 21. Structures of eicosapentanoic (47) and docosahexanoic acidacid ((48).). Recently, He et al. analyzed the influence of DHA on the locomotor activity in ethanol-treated Recently,Recently, HeHe etet al.al. analyzedanalyzed thethe influenceinfluence ofof DHADHA onon thethe locomotorlocomotor activityactivity inin ethanol-treatedethanol-treated HIV-1 transgenic rats [109]. The prevalence of alcohol use and alcohol abuse in infected individuals is HIV-1HIV-1 transgenictransgenic ratsrats [109].[109]. TheThe prevalenceprevalence ofof alalcoholcohol useuse andand alcoholalcohol abuseabuse inin infectedinfected individualsindividuals much higher, and numerous ethanol and HIV-1 viral proteins have synergistic effects on inflammation isis muchmuch higher,higher, andand numerousnumerous ethanolethanol andand HIV-1HIV-1 viralviral proteinsproteins havehave synergisticsynergistic effectseffects onon in the central nervous system [118–120]. HIV remains in the body in its latent form after HAART inflammationinflammation inin thethe centralcentral nervousnervous systemsystem [118–120].[118–120]. HIVHIV remainsremains inin thethe bodybody inin itsits latentlatent formform afterafter therapy and, as such, can induce neuroinflammation. DHA depletion has been found to be associated HAARTHAART therapytherapy and,and, asas such,such, cancan induceinduce neuroinfneuroinflammation.lammation. DHADHA depletiondepletion hashas beenbeen foundfound toto bebe with various neurological abnormalities, and its administration can have a neuroprotective effect. DHA associatedassociated withwith variousvarious neurologicalneurological abnormalities,abnormalities, andand itsits administrationadministration cancan havehave aa taken daily could reverse the effects of the ethanol negative effect on the locomotor activity in the neuroprotectiveneuroprotective effect.effect. DHADHA takentaken dailydaily couldcould reversereverse thethe effectseffects ofof thethe ethanolethanol negativenegative effecteffect onon thethe presence of HIV viral proteins. An in vivo study, using real-time quantitative PCR, showed that the locomotorlocomotor activityactivity inin thethe presencepresence ofof HIVHIV viravirall proteins.proteins. AnAn inin vivovivo study,study, usingusing real-timereal-time addition of DHA can reduce elevated levels of IL-6, IL-18, and increase the expression of NF-κB in the quantitativequantitative PCR,PCR, showedshowed thatthat thethe additionaddition ofof DHADHA cancan reducereduce elevatedelevated levelslevels ofof IL-6,IL-6, IL-18,IL-18, andand striatum. This proved the potential of this fish oil constituent as an adjuvant in HIV patients’ treatment increaseincrease thethe expressionexpression ofof NF-NF-κκBB inin thethe striatum.striatum. ThisThis provedproved thethe potentialpotential ofof thisthis fishfish oiloil constituentconstituent that can help in lowering the interactive effects of ethanol consumption during HIV infection. asas anan adjuvantadjuvant inin HIVHIV patients’patients’ treatmenttreatment thatthat cancan helphelp inin loweringlowering thethe interactiveinteractive effectseffects ofof ethanolethanol consumptionconsumption duringduring HIVHIV infection.infection.

2.9.2.9. OthersOthers ResorcyclicResorcyclic acidacid lactones,lactones, namelynamely radicicolradicicol ((4949,, FigureFigure 22)22) pochoninpochonin BB ((5050,, FigureFigure 22)22) andand CC ((5151,, FigureFigure 22)22) isolatedisolated fromfrom H.H. fuscoatrafuscoatra exhibitedexhibited aa 92–98%92–98% reactivationreactivation efficiencyefficiency ofof thethe latentlatent HIV-1HIV-1 relative to SAHA (subeoylanilide hydroxamic acid, vorinostat, HDAC inhibitor) and EC50 of 9.1, 39.6 relative to SAHA (subeoylanilide hydroxamic acid, vorinostat, HDAC inhibitor) and EC50 of 9.1, 39.6

Molecules 2019, 24, 3486 29 of 36

2.9. Others Resorcyclic acid lactones, namely radicicol (49, Figure 22) pochonin B (50, Figure 22) and C (51, MoleculesFigureMolecules 22 20192019) isolated,, 2424,, xx FORFOR from PEERPEER H. REVIEWREVIEW fuscoatra exhibited a 92–98% reactivation eﬃciency of the latent3333 HIV-1 ofof 4040 relative to SAHA (subeoylanilide hydroxamic acid, vorinostat, HDAC inhibitor) and EC50 of 9.1, and39.6and 6.3 and6.3 µMµM 6.3 [110].[110].µM[ 110 TheThe]. reactivationreactivation The reactivation strategystrategy strategy is,is, indeed,indeed, is, indeed, aa promisingpromising a promising strategystrategy strategy toto expungeexpunge to expunge thethe HIV-1HIV-1 the infectionHIV-1infection infection byby reactivatingreactivating by reactivating latentlatent viral latentviral loads,loads, viral loads,mainlymainly mainly inin CD4CD4 in ++ CD4 T-cells,T-cells,+ T-cells, whichwhich whichquicklyquickly quickly reboundrebound rebound whenwhen antiviralwhenantiviral antiviral treatmenttreatment treatment isis interrupted.interrupted. is interrupted. ItIt waswas notednoted It was thatthat noted allall activeactive that all compoundscompounds active compounds containcontain MichaelMichael contain acceptoracceptor Michael functionality.acceptorfunctionality. functionality. TheThe PKC-independentPKC-independent The PKC-independent mechanismmechanism mechanism ofof reactivationreactivation of reactivation ofof thethe of latentlatent the latent HIV-1HIV-1 HIV-1 remainsremains remains toto bebe to elucidated.beelucidated. elucidated.

FigureFigure 22. 22. StructuresStructures of of radicicol radicicol ( (4949),),), pochonin pochoninpochonin B BB ( (5050),), pochonin pochonin C C ( (5151).).

AA teamteam team ofof of researchersresearchers researchers ledled led byby Zhao byZhao Zhao isolatedisolated isolated newnew isoprenylatedisoprenylated new isoprenylated cyclohexanolscyclohexanols cyclohexanols fromfrom thethe from sponge-sponge- the associatedsponge-associatedassociated fungusfungus fungusTruncatellaTruncatellaTruncatella angustataangustata angustata namednamednamed truncateolstruncateols truncateols O-VO-V [111].[111]. O-V [In111In vitrovitro]. In vitrotestingtestingtesting showedshowed showed thatthat truncateolsthattruncateols truncateols OO andand O PP and ((5252 P andand (52 5353and,, FigureFigure53, Figure 2323),), analoguesanalogues 23), analogues bearingbearing bearing thethe alkynylalkynyl the alkynyl groupgroup groupinin thethe side inside the chain,chain, side exhibitchain,exhibit exhibit aa significantsignificant a signiﬁcant inhibitioninhibition inhibition towardtoward toward thethe HIV-1 theHIV-1 HIV-1 virusvirus virus withwith with ICIC50 IC50 values50valuesvalues ofof of39.039.0 39.0 µMµMµM andand and 16.116.1 16.1 µM,µM,µM, respectively.respectively. These These compounds compounds could could be be considered considered as as new new anti-HIV anti-HIV lead lead compounds compounds due due to to lower lower cytotoxicitycytotoxicity (CC (CC5050 >> 100100100 µM)µM)µM) inin in comparisoncomparison comparison withwith with thethe the positivepositive positive controlcontrol control efavirenzefavirenz (CC(CC 5050 === 40.640.640.6 µM).µM).µM).

FigureFigure 23.23. StructuresStructures of of truncateols truncateols O O ( (5252)) and and P P ( (5353).). 3. Future Directions in the Anti-HIV Marine Drug Development 3.3. FutureFuture DirectionsDirections inin thethe Anti-HIVAnti-HIV MarineMarine DrugDrug DevelopmentDevelopment Marine organisms have been acknowledged as a precious source of bioactive compounds that MarineMarine organismsorganisms havehave beenbeen acknowledgedacknowledged asas aa preciousprecious sourcesource ofof bioactivebioactive compoundscompounds thatthat may provide novel anti-HIV structures or lead structures for structural optimization. A large amount maymay provideprovide novelnovel anti-HIVanti-HIV structuresstructures oror leadlead strustructuresctures forfor structuralstructural optimization.optimization. AA largelarge amountamount of evidence from scientific research confirmed a high biological potential of these compounds to ofof evidenceevidence fromfrom scientificscientific researchresearch confirmedconfirmed aa hihighgh biologicalbiological potentialpotential ofof thesethese compoundscompounds toto treattreat treat serious diseases, including infective ones. Some of the marine-derived bioactive compounds seriousserious diseases,diseases, includingincluding infectiveinfective ones.ones. SomeSome ofof thethe marine-derivedmarine-derived bioactivebioactive compoundscompounds discovered much earlier have emerged with novel properties and potential applications after a decade discovereddiscovered muchmuch earlierearlier havehave emergedemerged withwith novenovell propertiesproperties andand potentialpotential applicationsapplications afterafter aa or two. Isolation and structural elucidation of compounds from marine organisms is not an easy decadedecade oror two.two. IsolationIsolation andand structuralstructural elucidatioelucidationn ofof compoundscompounds fromfrom marinemarine organismsorganisms isis notnot anan task and still carries challenges. Identification of all the compounds is a daunting task, especially easyeasy tasktask andand stillstill carriescarries challenges.challenges. IdentificationIdentification ofof allall thethe compoundscompounds isis aa dauntingdaunting task,task, especiallyespecially with regards to complex structural motifs that may be present in a single marine extract. Taxonomic withwith regardsregards toto complexcomplex structuralstructural motifsmotifs thatthat maymay bebe presentpresent inin aa singlesingle marinemarine extract.extract. TaxonomicTaxonomic knowledge is still insufficient to enable unambiguous species classification that can result in the false knowledgeknowledge isis stillstill insufficientinsufficient toto enableenable unambiguousunambiguous speciesspecies classificationclassification thatthat cancan resultresult inin thethe falsefalse prediction of chemical constituents and hamper structural analysis. Furthermore, a temporal lag predictionprediction ofof chemicalchemical constituentsconstituents andand hamperhamper structuralstructural analysis.analysis. Furthermore,Furthermore, aa temporaltemporal laglag between the discovery, chemical characterization, and associated pharmacological activities is quite betweenbetween thethe discovery,discovery, chemicalchemical characterization,characterization, anandd associatedassociated pharmacologipharmacologicalcal activitiesactivities isis quitequite common, and the majority of marine metabolites are usually tested for anticancer activity, whereas common,common, andand thethe majoritymajority ofof marinemarine metabolitesmetabolites areare usuallyusually testedtested forfor anticanceranticancer activity,activity, whereaswhereas anti-HIV and other possible biological effects are neglected or mostly not performed due to a lack of anti-HIVanti-HIV andand otherother possiblepossible biologicbiologicalal effectseffects areare neglectedneglected oror mostlymostly notnot performedperformed duedue toto aa lacklack ofof funding.funding. TargetedTargeted assaysassays andand inin vivovivo analysesanalyses areare similarlysimilarly performedperformed onlyonly forfor somesome ofof thethe potentialpotential candidates,candidates, whilewhile thethe translationtranslation intointo clinicalclinical triatrialsls remainsremains veryvery limited.limited. Thus,Thus, thethe financialfinancial gapgap isis certainlycertainly aa relevantrelevant factorfactor contributingcontributing toto thethe slowslow drugdrug developmentdevelopment processprocess inin thisthis area.area. InIn particular,particular, thethe developmentdevelopment ofof anti-HIVanti-HIV compounds,compounds, whichwhich actact byby mechanismsmechanisms thatthat differdiffer fromfrom existingexisting antivirals,antivirals, requiresrequires aa well-designedwell-designed andand fofocusedcused approachapproach toto studyingstudying thethe modemode ofof action.action. LibrariesLibraries shouldshould bebe createdcreated forfor specificallyspecifically defidefinedned crudecrude extracts,extracts, theirtheir correspondingcorresponding simplifiedsimplified

Molecules 2019, 24, 3486 30 of 36 funding. Targeted assays and in vivo analyses are similarly performed only for some of the potential candidates, while the translation into clinical trials remains very limited. Thus, the financial gap is certainly a relevant factor contributing to the slow drug development process in this area. In particular, the development of anti-HIV compounds, which act by mechanisms that differ from existing antivirals, requires a well-designed and focused approach to studying the mode of action. Libraries should be created for specifically defined crude extracts, their corresponding simplified fractions as well as for pure compounds for a well-balanced natural product discovery program. Additionally, there exist but few publications in which scientists have tried to modify known compounds of marine origin to improve their bioactivity. We are, however, continuously witnessing advancements in the deep-sea exploration technology, sampling strategies, genome sequencing, genome mining, genetic engineering, chemo-enzymatic synthesis, nanoscale NMR structure determination, and development and optimization of suitable fermentation strategies to ensure a continued supply of unique bioactive compounds from the oceans. Therefore, the grounds have been met for a broad, international effort based on scientific collaboration that would rely on well-equipped infrastructure and human resources as a prerequisite for a full advancement in the field and development of new drug candidates for the pharmaceutical market in the future.

Author Contributions: K.W. devised the main conceptual idea and, together with L.S. and Ž.P., wrote the manuscript parts related to medicinal chemistry. K.W. and Ž.P. performed literature searches and L.S. prepared the table. S.K.P. participated in the manuscript writing and wrote and discussed parts relevant for clinical applications, shaped the paper concept, and performed the final revision. Funding: We want to thank the Croatian Government and the European Union (European Regional Development Fund—the Competitiveness and Cohesion Operational Programme—KK.01.1.1.01) for funding this research through project Bioprospecting of the Adriatic Sea (KK.01.1.1.01.0002) granted to The Scientific Centre of Excellence for Marine Bioprospecting—BioProCro. We also acknowledge the project “Research Infrastructure for Campus-based Laboratories at the University of Rijeka,” co-financed by European Regional Development Fund (ERDF) and the University of Rijeka research grant uniri-biomed-18-133 (1277). Conflicts of Interest: The authors declare no conflict of interests.

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