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Expanding the Activity Spectrum of Antiviral Agents

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Expanding the Activity Spectrum of Antiviral Agents REVIEWS Drug Discovery Today Volume 24, Number 5 May 2019 Reviews POST SCREEN Expanding the activity spectrum of antiviral agents 1 1 2 1,3 Aleksandr Ianevski , Petter I. Andersen , Andres Merits , Magnar Bjørås and 1,2 Denis Kainov 1 Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7028, Norway 2 Institute of Technology, University of Tartu, Tartu 50090, Estonia 3 Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo 0027, Norway Broad-spectrum antivirals (BSAs) are agents that inhibit replication of several human viruses. Here, we review 108 approved, investigational, and experimental BSAs, for which safety profiles in humans are available. The most effective and tolerable BSAs could reinforce the arsenal of available antiviral therapeutics pending the results of further pre-clinical and clinical studies. Introduction 108 BSAs target 78 viruses Existing and emerging viral diseases are an ever-growing prob- The BSAs identified target 78 viruses from 24 assigned families, lem, particularly in developing countries. Vaccines and antiviral belonging to (–)single-stranded (ss)RNA, (+)ssRNA, double- drugs are powerful tools to combat viral diseases; however, most stranded (ds)RNA, ssRNA-reverse transcriptase (RT), ssDNA, of these therapeutics target a single virus. By contrast, BSAs are ssDNA-RT, dsDNA, or dsDNA-RT virus groups (Fig. 1; Table able to inhibit different viral infections, because most viruses S2 in the Supplemental information online). Antiparasitic nita- follow common pathways to replicate inside a host cell [1]. zoxanide has the broadest spectrum of antiviral activity, be- Academic institutions and pharmaceutical companies have urged cause it inhibits viruses belonging to the (–)ssRNA, (+)ssRNA, the discovery and development of such BSAs to overcome time dsRNA, ssRNA-RT, dsDNA, and dsDNA-RT groups. Glycyrrhizin, and cost issues associated with the development of virus-specific a sweet-tasting constituent of Glycyrrhiza glabra (liquorice) drugs and vaccines [2–7]. root, and niclosamide, an orally available immunosuppressant To identify potential BSAs, we reviewed approved and investi- used to treat tapeworm infestations, also inhibit several (–) gational safe-in-man antiviral agents using drug bank and clinical ssRNA, (+)ssRNA, dsDNA and ssRNA-RT viruses in vitro and, trials websites, respectively. In addition, we reviewed investiga- in some cases, in vivo [9–11]. Favipiravir is an anti-influenza tional and approved safe-in-man agents, including antibacterials, drug that has shown antiviral effects against many different (–) antimalarials, antiparasitics, immune-modulating, antidepres- and (+)ssRNA viruses. sants, antiemetics, and so on, for which antiviral activities have Importantly, these and other BSAs have been tested against been reported in PubMed. By excluding vaccines and interferons, some but not all 78 viruses in vitro. In particular, 55 BSAs were we identified 59 molecules that inhibit replication of several recently probed against 13 different viruses [influenza A virus viruses in humans [8]. Recently, some of the experimental antiviral (FLUAV), Rift Valley fever virus (RVFV), Human metapneumo- agents entered clinical trials and became investigational. At the virus (HMPV), echovirus 1 (EV1), chikungunya virus (CHIKV), same time, novel antiviral activities have been reported for some of Ross River virus (RRV), Zika virus (ZIKV), hepatitis C virus these as well as other agents, expanding the list of available BSAs to (HCV), Sindbis virus (SINV), HIV-1, cytomegalovirus (CMV), 108 (Table S1 and Fig. S1 in the Supplemental information online). hepatitis B virus (HBV), and herpes simplex virus type 1 (HSV- 1)]. Novel activities were identified for dalbavancin against Corresponding author: Kainov, D. ([email protected]) EV1; for ezetimibe against HIV-1, SINV, and ZIKV; for azaci- 1359-6446/ã 2019 Elsevier Ltd. All rights reserved. 1224 www.drugdiscoverytoday.com https://doi.org/10.1016/j.drudis.2019.04.006 Drug Discovery Today Volume 24, Number 5 May 2019 REVIEWS POST SCREEN Reviews Drug Discovery Today FIGURE 1 In vitro activities of 108 safe-in-man broad-spectrum antivirals (BSAs). Viruses are clustered by virus group. BSAs are ranged from the highest to lowest number of targeted viruses. Blue shading indicates that antiviral activity has been reported for the BSA, whereas gray shading indicates that antiviral activity has not been either reported or studied. Abbreviations: ds, double-stranded; RT, reverse transcriptase; ss, single-stranded. tidine, cyclosporine, minocycline, and ritonavir against RVFV; and nitazoxanide against HMPV [8,12].To further expand a for oritavancin against RVFV, HMPV, and HCV; for cidofovir, spectrum of these and other BSA activities, the library of 108 dibucaine, azithromycin, gefitinib, minocycline, and pirlin- BSAs could be readily made available and tested against these dole against HCV; and for azacitidine, itraconazole, lopinavir, and other viruses. www.drugdiscoverytoday.com 1225 REVIEWS Drug Discovery Today Volume 24, Number 5 May 2019 BSA structures scaffolds could lead to more efficient treatment modalities and C-SPADE and multidimensional scaling analyses [13,14] of BSAs provide new knowledge of virus–host interactions. Natural pro- structures revealed that many BSAs have similar scaffolds. These ducts could represent a source of BSAs with new scaffolds [15]. include: acyclovir, famciclovir, filociclovir, ganciclovir and vala- ciclovir; imatinib, erlotinib, gefitinib, and dasatinib; telavancin, Mechanisms of actions of BSAs dalbavancin, oritavancin, and teicoplanin; alisporivir and cyclo- Unfortunately, we know little about mechanisms of action (MOAs) sporine; minocycline and doxycycline; lovastatin and simvastatin; oftheseBSAs.Inparticular,weknowpotentialviralorhosttargetsfor raloxifene and amiodarone; ritonavir and lopinavir; esomeprazole only 91agents(Table S1and Fig.S2intheSupplementalinformation Reviews and omeprazole; camptothecin and topotecan; trifluridine and N- online) [6,8,16,17]. Examples of virus-directed BSAs are nucleotide MCT; and quinine, brequinar, amodiaquine, hydroxychloro- and nucleoside analogs, which inhibit viral RTs, and RNA or DNA POST SCREEN quine, and chloroquine BSAs (Fig. 2). The structural constrains polymerases, given that host factors could be involved in activation limit the diversity of BSAs. Finding antiviral agents with novel of some of the drugs [18]. In particular, tenofovir and lamivudine Drug Discovery Today FIGURE 2 Dendrogram showing the structural relationship between 106 out of 108 broad-spectrum antivirals (BSAs). Given their complex structures, CYT107 (IL7) and aprotinin were excluded from the analysis. 1226 www.drugdiscoverytoday.com Drug Discovery Today Volume 24, Number 5 May 2019 REVIEWS inhibit RTs. Ribavirin, favipiravir, sofosbuvir, 4-hydroxyphenylre- CRISPR/Cas9 or other techniques that enable the identification tinamide, remdesivir, and BCX4430 inhibit viral RNA polymerases and/or validation of antiviral targets [47,48]. [19]. Trifluridine, vidarabine, N-methanocarbathymidine, mariba- vir, acyclovir, famciclovir, ganciclovir, filociclovir, valaciclovir, Clinical relevance of BSAs cidofovir, brincidofovir, and tenofovir block viral DNA polymerases Many safe-in-man BSAs have been shown to have antiviral activity [20], whereas azacitidine inhibits RT, and DNA and RNA poly- in vitro, but only a fraction of these agents has been tested in merases. Examples of non-nucleotide/non-nucleoside virus-direct- animal models (Table S1 in the Supplemental information online). ed BSAs include inhibitors of viral polymerases (foscarnet), helicases Testing activity of BSAs in mouse models could demonstrate (pirlindole, dibucaine, fluoxetine, and formoterol), terminases whether the drug concentration used for the primary disease (letermovir) and proteases (lopinavir, ritonavir, nelfinavir, and bro- indication could be tolerable and effective for secondary disease mocriptine). However, viruses could develop resistance to both indication. However, there are no animal models for some viruses. nucleotide and nucleoside analogs under selective pressure. In these cases, the testing of BSAs in vivo could be bypassed. POST SCREEN Host-directed BSAs could be subclassified based on the stage of The crucial point for the next step in safe-in-man BSA develop- virus replication they inhibit [16,19,21–25]. For example, 4-ami- ment is the availability of human clinical, pharmacokinetics and noquinolines (chloroquine, hydroxychloroquine, and amodia- safety data of the repurposed drugs [17,49]. For example, safety Reviews quine), proton-pump inhibitors (omeprazole and esomeprazole), data on the anti-influenza drug favipiravir were used in clinical Mcl-1 inhibitors (obatoclax), as well as calcium channel blockers Phase II studies against EBOV (NCT02329054 and NCT02662855). (verapamil and bepridil) prevent virus entry into host cells [26,27]. Another interesting example is the antimalarial chloroquine, the In addition, glycopeptides (teicoplanin, dalbavancin, oritavancin, safety data of which were used for anti-CHIKV, DENV, HCV, and and telavancin), serine protease inhibitors (camostat and nafamo- HIV-1 Phase II studies (NCT00391313, NCT02058173, stat), proteasome inhibitors (bortezomib) and niclosamide pre- NCT00308620, and NCT00849602, respectively). vent endocytosis of viruses [28]. Another option would be to combine BSAs to obtain even Cyclin-dependent kinase inhibitors
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