New Hopes for Drugs Against COVID-19 Come from the Sea

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Editorial New Hopes for Drugs against COVID-19 Come from the Sea

Orazio Taglialatela-Scafati

Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via D. Montesano 49, I-80131 Naples, Italy; [email protected]; Tel.: +39-081678509

The latest chapter of the historic battle of humans against pathogenic microbes is the severe acute respiratory syndrome (SARS)-like coronavirus-2 (SARS-CoV-2), responsible for COVID-19, a respiratory disease declared a global pandemic by the WHO on March 11, 2020. Less than one year later, at the beginning of February 2021, nearly 104 million cases and 2.3 million deaths have been reported worldwide [1], but the effects on the global economy (and on our psychological wellbeing) will probably last for years. The progressive approval and utilization of effective vaccines, including two unprece- dented mRNA-based ones, is very good news that was largely unexpected only a few months ago, and that could allow us to watch with a cautious optimism to the months to come. However, the full control of COVID-19 cannot rely only on vaccines; it will also require efficacious therapeutics, which could possibly be used to face future related infec- tions more efficiently. Although several molecules are currently undergoing clinical trials, the single FDA-approved drug is remdesivir [2], alone or in combination with baricitinib, indicated to treat severe COVID-19 cases in adults and children (≥12 years old). Repurposing existing drugs has been a very popular strategy among scientists search- ing for possible COVID-19 treatments, especially those trying to block the recognition between the SARS-CoV-2 spike glycoprotein and the cellular angiotensin-converting en- zyme 2 (ACE2). Additionally, many anti-inflammatory and anticancer drugs have been repurposed to inhibit the massive inflammatory response (the so-called cytokine storm) Citation: Taglialatela-Scafati, O. New resulting from the SARS-CoV-2 infection. Hopes for Drugs against COVID-19 In the frame of this global endeavor, the contribution of researchers working on Come from the Sea. Mar. Drugs 2021, marine natural compounds has been very significant. Kim et al. have reported [3] that 19 , 104. https://doi.org/10.3390/ lambda-carrageenan (λ-CGN), sulfated galactose-based polysaccharides purified from md19020104 marine red algae, efficiently inhibited SARS-CoV-2 with a submicromolar activity, reducing the expression of viral proteins in cell lysates and suppressing progeny virus production Received: 9 February 2021 in culture supernatants. Most likely, these polymeric compounds act by targeting viral Accepted: 9 February 2021 Published: 11 February 2021 attachments to cell surface receptors, thus preventing virus entry. Marine Drugs has published six articles on marine molecules with potential against

Publisher’s Note: MDPI stays neutral coronavirus, including three review articles [4–6] and three research papers [7–9]. In two of with regard to jurisdictional claims in these [7,8], the authors suggest that another marine natural polymer, the inorganic polyP, published maps and institutional afﬁl- abundantly present in marine bacteria, is worthy of further investigation for its activity in iations. strengthening the mucin barrier and inhibiting viral attachment to the cells. Another very promising result has been reported in a preprint paper by Gerwick, O’Donoghue and Payne [10]. They have identiﬁed the marine cyanobacterial depsipeptide gallinamide A/symplostatin 4 (1, Figure1) and some synthetic analogues as potent (in the picomolar range) and selective inhibitors of cathepsin L. This lysosomal cysteine protease Copyright: © 2021 by the author. Licensee MDPI, Basel, Switzerland. is utilized by coronaviruses to release RNA material inside the cell and, consequently, its This article is an open access article blockade results in a marked inhibition of SARS-CoV-2 infection in vitro. distributed under the terms and However, probably the most exciting discovery was published at the end of January conditions of the Creative Commons 2021 in Science [11]. White, Rosales et al. have reported that, in studies in human cells, Attribution (CC BY) license (https:// plitidepsin (dehydrodidemnin B, 2), a depsipeptide originally isolated from the tunicate Ap- ® creativecommons.org/licenses/by/ lidium albicans and marketed with the name Aplidin by Pharmamar, largely outperformed 4.0/). remdesivir against SARS-CoV-2. Plitidepsin target is the human protein eEF1A, whose

Mar. Drugs 2021, 19, 104. https://doi.org/10.3390/md19020104 https://www.mdpi.com/journal/marinedrugs Mar. Drugs 2021, 19, 104 2 of 2

expression is related to cancer insurgence, but which is also involved in the interaction with the coronavirus nucleocapsid protein during the viral infection. The researchers tested the drug in two different mouse models: in mice that were administered plitidepsin shortly before being infected with SARS-CoV-2, the drug signiﬁcantly reduced viral load (similarly to remdesivir) and lung inﬂammation (much better than remdesivir) compared with con- Mar. Drugs 2021, 19, x FOR PEER REVIEW trols. Plitidepsin is approved for use against multiple myeloma, and its2 repurposing of 3 could

allow the compound to directly enter phase III clinical trials against COVID-19.

Figure 1. TheFigure chemical 1. The structures chemical of structuresgallinamide of gallinamideA (1) and plitidepsin A (1) and ( plitidepsin2). (2).

However, probablyThese the results most once exciting more disc certifyovery that was sea published organisms/micro-organisms at the end of January are incredibly 2021 in Scienceprolific [11]. White, sources Rosales of bioactive et al. have secondary reported metabolites, that, in studies and they in arehuman a strong cells, encouragement plitidepsin (dehydrodidemninfor the marine natural B, 2), a product depsipeptide scientific originally community isolated to continuefrom the intunicate the efforts to exploit Aplidium albicansthis uniqueand marketed resource. with the name Aplidin® by Pharmamar, largely outperformed remdesivir against SARS-CoV-2. Plitidepsin target is the human protein Funding: This research received no external funding. eEF1A, whose expression is related to cancer insurgence, but which is also involved in the interactionConflicts with the of coronavirus Interest: The nucleocaps author declaresid protein no conflict during of interest. the viral infection. The researchers tested the drug in two different mouse models: in mice that were References administered plitidepsin shortly before being infected with SARS-CoV-2, the drug 1. WHO Coronavirussignificantly Disease reduced (COVID-19) viral Dashboard. load (similarly Available to remdesivir) online: https://covid19.who.int/ and lung inflammation (accessed (much on 5 February 2021). 2. FDA Approvesbetter First than Treatment remdesivir) for COVID-19. compared Available with online:contro https://www.fda.gov/news-events/press-announcements/fda-ls. Plitidepsin is approved for use against approves-first-treatment-covid-19multiple myeloma, and(accessed its repurposing on 5 February coul 2021).d allow the compound to directly enter 3. Jang, Y.; Shin, H.; Lee, M.K.; Kwon, O.S.; Shin, J.S.; Kim, Y.; Kim, C.W.; Lee, H.-R.; Kim, M. Antiviral activity of lambda-carrageenan phase III clinical trials against COVID-19. against influenza viruses and severe acute respiratory syndrome coronavirus 2. Sci. Rep. 2021, 11, 821. [CrossRef] [PubMed] 4. Fitton, J.H.; Park,These A.Y.; Karpiniec, results once S.S.; Stringer,more certify D.N. Fucoidanthat sea andorganisms/micro-organisms lung function: Value in viral infection.are incrediblyMar. Drugs 2021, 19, 4. [CrossRef][prolificPubMed sources] of bioactive secondary metabolites, and they are a strong encouragement 5. Zahran, E.M.;for Albohy,the marine A.; Khalil,natural A.; product Ibrahim, scientific A.H.; Ahmed, commu H.A.;nity El-Hossary,to continue E.M.; in the Bringmann, efforts to G.;exploit Abdelmohsen, U.R. Bioactivity potentialthis unique of marine resource. natural products from Scleractinia-associated microbes and in silico anti-SARS-COV-2 evaluation. Mar. Drugs 2020, 18, 645. [CrossRef][PubMed] 6. Barre, A.; VanFunding: Damme, This E.J.M.; research Simplicien, received M.; no Benoist, external H.; funding. Rougé, P. Man-Specific, GalNAc/T/Tn-Specific and Neu5Ac-Specific seaweed lectins as glycan probes for the SARS-CoV-2 (COVID-19) coronavirus. Mar. Drugs 2020, 18, 543. [CrossRef][PubMed] Conflicts of Interest: The author declares no conflict of interest. 7. Müller, W.E.G.; Neufurth, M.; Wang, S.; Tan, R.; Schroder, H.C.; Wang, X. Morphogenetic (mucin expression) as well as potential anti-corona viral activity of the marine secondary metabolite polyphosphate on A549 cells. Mar. Drugs 2020, 18, 639. [CrossRef] [PubMed] References 8. Neufurth, M.; Wang, X.; Wang, S.; Schroder, H.C.; Müller, W.E.G. Caged dexamethasone/quercetin nanoparticles, formed of the 1. WHO Coronavirusmorphogenetic Disease (COVID-19) active inorganic Dashboard. polyphosphate, Available on areline: strong https://covid19.who.int/ inducers of MUC5AC. (accessedMar. Drugs on 52021 February, 19, 64. 2021). [CrossRef ][PubMed] 2. FDA 9. ApprovesGentile, D.; Patamia,First V.; Scala, A.;Treatment Sciortino, M.T.; Piperno,for A.; Rescifina,COVID-19. A. PutativeAvailable inhibitors of SARS-CoV-2online: main protease https://www.fda.gov/news-events/press-annofrom a library of marine naturaluncements/fda-approves-first-treatment-co products: A virtual screening and molecularvid-19 modeling (accessed study. onMar. 5 February Drugs 2021 2021)., 19 , 64. [CrossRef] 3. Jang, Y.; Shin,10. Ashhurst,H.; Lee, A.S.;M.K.; Tang, Kwon, A.H.; O.S.; Fajtova, Shin, P.; Yoon,J.S.; M.;Kim, Aggarwal, Y.; Kim, A.; C.W.; Stoye, Lee, A.; Larance, H.-R.; M.;Kim, Beretta, M. Antiviral L.; Drelich, activity A.; Skinner, of D.; et al. Potent lambda-carrageenanin vitro against anti-SARS-CoV-2 influenza viruses activity and by gallinamidesevere acute A respiratory and analogues syndrome via inhibition coronavirus of cathepsin 2. Sci. L. Rep.bioRxiv 20212020, 11,, Preprint.821, [CrossRef] doi:10.1038/s41598-020-80896-9.11. White, K.M.; Rosales, R.; Yildiz, S.; Kehrer, T.; Miorin, L.; Moreno, E.; Jangra, S.; Uccellini, M.B.; Rathnasinghe, R.; Coughlan, L.; et al. 4. Fitton, J.H.; Park.Plitidepsin A.Y.; Karpiniec, has a potent S.S.; Stringer, preclinical D.N. efficacy Fucoidan against and SARS-CoV-2 lung function: by targeting Value thein viral host infection. protein eEF1A. Mar. DrugsScience 20212021,, 19 in, press. [CrossRef] 4, doi:10.3390/md19010004. 5. Zahran, E.M.; Albohy, A.; Khalil, A.; Ibrahim, A.H.; Ahmed, H.A.; El-Hossary, E.M.; Bringmann, G.; Abdelmohsen, U.R. Bioactivity potential of marine natural products from Scleractinia-associated microbes and in silico anti-SARS-COV-2 evaluation. Mar. Drugs 2020, 18, 645, doi:10.3390/md18120645. 6. Barre, A.; Van Damme, E.J.M.; Simplicien, M.; Benoist, H.; Rougé, P. Man-Specific, GalNAc/T/Tn-Specific and Neu5Ac-Specific seaweed lectins as glycan probes for the SARS-CoV-2 (COVID-19) coronavirus. Mar. Drugs 2020, 18, 543, doi:10.3390/md18110543. 7. Müller, W.E.G.; Neufurth, M.; Wang, S.; Tan, R.; Schroder, H.C.; Wang, X. Morphogenetic (mucin expression) as well as potential anti-corona viral activity of the marine secondary metabolite polyphosphate on A549 cells. Mar. Drugs 2020, 18, 639; doi:10.3390/md18120639. 8. Neufurth, M.; Wang, X.; Wang, S.; Schroder, H.C.; Müller, W.E.G. Caged dexamethasone/quercetin nanoparticles, formed of the morphogenetic active inorganic polyphosphate, are strong inducers of MUC5AC. Mar. Drugs 2021, 19, 64; doi:10.3390/md19020064.