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Drug Repurposing for Viral Infectious Diseases: How Far Are We?

2018; Elsevier BV; Volume: 26; Issue: 10 Linguagem: Inglês

10.1016/j.tim.2018.04.004

1878-4380

Beatrice Mercorelli, Giorgio Palù, Arianna Loregian,

CRISPR and Genetic Engineering

Repurposing existing drugs is an emerging strategy for expediting the approval of effective and safe therapeutics, such as for the treatment of orphan drug diseases. New indications for antiviral activity can be identified for molecules of different origins showing repurposing potential by acting against a previously known target or a new antiviral target. Innovative approaches for target validation (e.g., gene editing by CRISPR/Cas9) and new experimental models (e.g., organoids) allowed the identification of novel antiviral agents and the unraveling of molecular pathways underlying viral pathogenesis. Drug repurposing has successfully identified promising candidate drugs that can open new therapeutic avenues to counteract current viral pathogens and possible emerging viruses. Despite the recent advances in controlling some viral pathogens, most viral infections still lack specific treatment. Indeed, the need for effective therapeutic strategies to combat 'old', emergent, and re-emergent viruses is not paralleled by the approval of new antivirals. In the past years, drug repurposing combined with innovative approaches for drug validation, and with appropriate animal models, significantly contributed to the identification of new antiviral molecules and targets for therapeutic intervention. In this review, we describe the main strategies of drug repurposing in antiviral discovery, discuss the most promising candidates that could be repurposed to treat viral infections, and analyze the possible caveats of this trendy strategy of drug discovery. Despite the recent advances in controlling some viral pathogens, most viral infections still lack specific treatment. Indeed, the need for effective therapeutic strategies to combat 'old', emergent, and re-emergent viruses is not paralleled by the approval of new antivirals. In the past years, drug repurposing combined with innovative approaches for drug validation, and with appropriate animal models, significantly contributed to the identification of new antiviral molecules and targets for therapeutic intervention. In this review, we describe the main strategies of drug repurposing in antiviral discovery, discuss the most promising candidates that could be repurposed to treat viral infections, and analyze the possible caveats of this trendy strategy of drug discovery. The identification of new targets for chemotherapeutic intervention is often not paralleled by the development and licensing of new drugs. Antiviral agents for treating viral infectious diseases are not an exception. From 2012 to 2017, only 12 new antivirals have been approved by the Food and Drug Administration (FDA) in the USA, of which 8 are for the treatment of hepatitis C virus (HCV)-related pathologies and 2 are combinations of anti-human immunodeficiency virus (HIV) drugs (www.fda.gov). On the other hand, governments and the World Health Organization (WHO) have to deal with critical (re)emerging viruses, characterized by pandemic potential and responsible for alarming outbreaks in recent years, which still lack specific treatment, such as Zika virus (ZIKV), Ebola virus (EBOV), and Middle East respiratory syndrome coronavirus (MERS-CoV). A drug discovery approach that has recently become very popular is drug repurposing (DR), which consists of giving old drugs a new indication by exploring new molecular pathways and targets for intervention [1Jones L.H. Bunnage M.E. Applications of chemogenomic library screening in drug discovery.Nat. Rev. Drug Discov. 2017; 16: 285-296Crossref PubMed Scopus (128) Google Scholar, 2Strittmatter S.M. Overcoming drug development bottlenecks with repurposing: old drugs learn new tricks.Nat. Med. 2014; 20: 590-591Crossref PubMed Scopus (146) Google Scholar]. DR applied to viral infectious diseases takes into account different strategies by integrating both screenings of bioactive small-molecule collections and computational methods (in silico screenings, mining of database with transcriptomic profiles, etc.) in order to find a molecule, a pathway, or a biological activity that could be recycled in fighting a viral pathogen. Beyond the unquestionable economic advantage derived from such an approach in the drug development process, repurposed drugs can quickly enter clinical trials or be employed for compassionate use, especially in the case of viral diseases lacking of specific treatment. Moreover, DR represents a constant source of new knowledge in virus biology as well as of molecules with previously undescribed antiviral properties that can be further used as molecular tools in uncovering molecular mechanisms of virus replication and pathogenesis. In many cases, DR points out previously unexplored cellular pathways, turning them into targets for new therapeutic strategies, even if the identified molecules cannot be introduced in clinical therapy. In this review, we describe the most meaningful results of this 'from bed to bench' approach, discuss the most promising drugs that could be repurposed to treat viral infections, and analyze the possible caveats of this trendy strategy of drug discovery, whose advantages and pitfalls are summarized in Table 1.Table 1Advantages and Pitfalls of a Drug Repurposing Approach for Antiviral Drug DiscoveryAdvantagesPitfallsLow cost and less time-consuming (essential for the development of drugs to treat neglected diseases)Target identification can be circuitous, and identified drugs may show polypharmacologyPossibility to skip preclinical trials (no animal studies) and to directly enter phase 2 clinical trialsDue to the high doses employed in the screenings, toxic drugs can be initially misidentified as activePotential for combination strategies with the possibility to delay or reduce resistance associated with monotherapyEffective concentrations are often higher than the plasma levels achievable in humansOften analogs (together with pharmacological information) are already available for testingMedicinal chemistry to design more potent analogs is not applicable without losing repurposing potentialAcademic/small laboratories can be determinant in the drug-discovery processIdentified drugs are often under intellectual property and/or programs that make them unavailable or unattractive for other pharmaceutical companies that could take over the further development and costs of clinical trialsFormulations and manufacturing chains are already established for the large-scale production (launching costs are avoided) Open table in a new tab Three different scenarios of antiviral DR can be identified depending on whether the repurposed molecule has previously known antiviral activity (Figure 1, Key Figure): (i) Same target – new virus. The first option is when an antiviral drug that is known to target a specific viral or cellular function/pathway is found to possess activity against other viruses. The antiviral activity relies on structural homology and common enzymatic features of the viral target or on shared pathways exploited for virus replication. Viral RNA polymerase inhibitors such as favipiravir and sofosbuvir (approved for the treatment of influenza virus and HCV infections, respectively) showed repurposing potential against EBOV and ZIKV (see below). Another example is represented by drugs (e.g., chloroquine) that interfere with the late-stage entry process of viruses, such as filoviruses and coronaviruses, which exploit cellular endocytic pathways to enter the host cell. (ii) Same target – new indication. This occurs when a pharmacological target (i.e., a protein or a pathway that can be modulated by an approved drug) is found to be essential in a pathogenic process associated with a viral infection. In this case, the approved drug can be exploited also as an antiviral therapeutic agent (new indication). The case is exemplified by the anticancer drug imatinib that inhibits cellular Abelson (ABL) kinase and was found to be also active against pathogenic coronaviruses [3Coleman C.M. et al.Abelson kinase inhibitors are potent inhibitors of severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus fusion.J. Virol. 2016; 90: 8924-8933Crossref PubMed Scopus (217) Google Scholar]. (iii) New target – new indication. This occurs when an approved drug with established bioactivity in a specific pathway or mechanism is found to have a new molecular target (i.e., it shows polypharmacology, see Glossary) which is essential for virus replication. Examples are antimicrobial agents (e.g., teicoplanin, ivermectin, itraconazole, and nitazoxanide) that were found to have a target also in virus-infected cells, whose inhibition has detrimental effects on viral replication [4Colson P. Raoult D. Fighting viruses with antibiotics: an overlooked path.Int. J. Antimicrob. Agents. 2016; 48: 349-352Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 5Strating J.R.P.M. et al.Itraconazole inhibits enterovirus replication by targeting the oxysterol-binding protein.Cell Rep. 2015; 10: 600-615Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar]. Drugs with repurposing potential against viral diseases have been identified mostly by the screening of small-molecule libraries consisting of drugs, both approved and developmental, and other compounds with known bioactivity, including compounds of natural origin. Most of these libraries are available at public institutions or commercially; however, a number of proprietary or in-house-made collections also exist, often consisting of only one class of drugs (e.g., kinase or apoptosis inhibitors, etc.) and can be useful for target deconvolution. Table 2 lists the drug collections most widely used in antiviral DR. In the past 5–10 years, partnerships between public and private institutions have been strongly encouraged by governments to expedite the identification of new candidate drugs, in particular for orphan diseases, and several pharmaceutical companies have opened their proprietary collections to collaboration programs with academic research groups [6Loregian A. Palù G. How academic labs can approach the drug discovery process as a way to synergize with big pharma.Trends Microbiol. 2013; 21: 261-264Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar].Table 2Small-Molecule Libraries Used in Antiviral Drug RepurposingLibrary (Vendor)DescriptionaA more detailed description of some of these libraries can be found in [1].RefsSCREEN-WELL FDA-Approved drugs Library (Enzo Life Sciences)774 approved drugs8Barrows N.J. et al.A screen of FDA-approved drugs for inhibitors of Zika virus infection.Cell Host Microbe. 2016; 20: 259-270Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar, 47de Wilde A.H. et al.Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture.Antimicrob. Agents Chemother. 2014; 58: 4875-4884Crossref PubMed Scopus (581) Google Scholar, 69van de Klundert M.A.A. et al.Identification of FDA-approved drugs that target hepatitis B virus transcription.J. Viral Hepat. 2016; 23: 191-201Crossref PubMed Scopus (15) Google ScholarLibrary Of Pharmacologically Active Compounds (LOPAC, Sigma-Aldrich)1280 bioactive compounds including FDA-approved drugs9Xu M. et al.Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.Nat. Med. 2016; 22: 1101-1107Crossref PubMed Scopus (532) Google Scholar, 66Mukhopadhyay R. et al.Efficacy and mechanism of action of low dose emetine against human cytomegalovirus.PLoS Pathog. 2016; 12e1005717Crossref PubMed Scopus (49) Google ScholarBioactive Compound Library(Selleck Chemicals)>2000 bioactive compounds including FDA-approved drugs13Rausch K. et al.Screening bioactives reveals nanchangmycin as a broad spectrum antiviral active against Zika virus.Cell Rep. 2017; 18: 804-815Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar, 25Wang S. et al.Screening of FDA-approved drugs for inhibitors of Japanese encephalitis virus infection.J. Virol. 2017; 91e01055-17Crossref PubMed Scopus (91) Google Scholar, 47de Wilde A.H. et al.Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture.Antimicrob. Agents Chemother. 2014; 58: 4875-4884Crossref PubMed Scopus (581) Google ScholarPrestwick Library1280 bioactive compounds including FDA-approved drugs and candidate drugs14Zhou T. et al.High-content screening in hPSC-neural progenitors identifies drug candidates that inhibit Zika virus infection in fetal-like organoids and adult brain.Cell Stem Cell. 2017; 21: 274-283Abstract Full Text Full Text PDF PubMed Scopus (180) Google ScholarSpectrum Collection(Microsource)2320–2560 bioactive compounds including FDA-approved drugs48Chan J.F.W. et al.Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus.J. Infect. 2013; 67: 606-616Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar, 62Mercorelli B. et al.Drug repurposing approach identifies inhibitors of the prototypic viral transcription factor IE2 that block human cytomegalovirus replication.Cell Chem. Biol. 2016; 23: 340-351Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 63Gardner T.J. et al.Development of a high-content screen for the identification of inhibitors directed against the early steps of the cytomegalovirus infectious cycle.Antiviral Res. 2015; 113: 49-61Crossref PubMed Scopus (33) Google ScholarUCSF Small Molecule Discovery Center Library2177 bioactive compounds including FDA-approved drugs10Retallack H. et al.Zika virus cell tropism in the developing human brain and inhibition by azithromycin.Proc. Natl. Acad. Sci. U. S. A. 2016; 113: 14408-14413Crossref PubMed Scopus (367) Google ScholarNational Institute of Health (NIH) Clinical Collection Library and Chemical Genomics Center (NCCGC)>7600 bioactive compounds including FDA-approved drugs and candidate drugs5Strating J.R.P.M. et al.Itraconazole inhibits enterovirus replication by targeting the oxysterol-binding protein.Cell Rep. 2015; 10: 600-615Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar, 16Adcock R.S. et al.Evaluation of anti-Zika virus activities of broad-spectrum antivirals and NIH clinical collection compounds using a cell-based, high-throughput screen assay.Antiviral Res. 2017; 138: 47-56Crossref PubMed Scopus (103) Google Scholar, 26Gastaminza P. et al.Unbiased probing of the entire hepatitis C virus life cycle identifies clinical compounds that target multiple aspects of the infection.Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 291-296Crossref PubMed Scopus (97) Google Scholar, 37Kouznetsova J. et al.Identification of 53 compounds that block Ebola virus-like particle entry via a repurposing screen of approved drugs.Emerg. Microbes Infect. 2014; 3: e84Crossref PubMed Scopus (40) Google Scholar, 75Huang R. et al.The NCGC pharmaceutical collection: a comprehensive resource of clinically approved drugs enabling repurposing and chemical genomics.Sci. Transl. Med. 2011; 380ps16Crossref PubMed Scopus (328) Google Scholara A more detailed description of some of these libraries can be found in 1Jones L.H. Bunnage M.E. Applications of chemogenomic library screening in drug discovery.Nat. Rev. Drug Discov. 2017; 16: 285-296Crossref PubMed Scopus (128) Google Scholar. Open table in a new tab Despite the restricted number of available collections, and the fact that often the same drugs are present in various libraries, in several cases different outcomes for the same viral pathogen have been obtained. A possible explanation is the different experimental setup used, including differences in cell type, virus strain, dose, readout method, and so on. Conversely, by screening different libraries, the same drugs were independently identified in some cases (e.g., for MERS-CoV, see below). Finally, virtual screening of chemical structures can also be performed to find new potential antiviral drugs; however, this approach is dependent upon the availability of structural information and a priori knowledge of the target. It is not usually required in DR screenings aimed at the discovery of new antiviral drugs to validate a target before the screening; in fact, an ex-post target validation, and even identification, is possible once an active molecule has been identified. Thus, DR screenings can mainly undertake two different experimental approaches: (i) unknown target – phenotypic assay, or (ii) known target − mechanism-based assay. In the first case, the target is generally unknown, and a phenotypic assay is employed for the identification of hit compounds. Phenotypic assays are based on a readout that is synonymous with antiviral activity and can be easily monitored in a high-throughput format. For example, the protection of infected cell monolayers by virus-induced cytopathic effect or the detection of a late-expressed, structural viral protein (envelope protein in most cases) are the most frequently exploited. After hit identification by phenotypic assay, the next step is the identification and validation of the target (a protein, a pathway, etc., which sometimes can be deduced from the mechanism of action of the identified hit compound). The validation is required to demonstrate that the target is indeed essential for virus replication and/or pathogenesis and is subordinated to the demonstration that its modulation leads to protection from virus infection and inhibition of virus-associated pathogenic effects. Experimental approaches for antiviral target validation can be exemplified by genetic knockdown through RNA interference, gene editing by CRISPR/Cas9 system, mutational analysis, and the use of pharmacological inhibitors (if available). All of these can be evaluated in cultured cells, in organoids, in ex vivo experimental models, as well as in animal models. Finally, when possible, a clinical validation on patient-derived samples or data can also be performed. Indeed, when a routinely employed drug is found to be potentially effective in the treatment of a viral infection, a possible positive correlation between drug administration in target patients and inhibition of the viral infection can be retrospectively analyzed in clinical studies. Alternatively, in mechanism-based DR screenings, target validation is mandatory prior to the screening design. Most frequent targets are druggable viral or cellular enzymes or receptors. The experimental setup in mechanism-based assays is specifically designed to identify molecules able to interfere with a particular process previously identified as essential for productive virus replication or involved in viral pathogenesis. Assays based on a specific mechanism, that is, inhibition of a transcription factor, protection from apoptosis by interfering with a specific activating mechanism, or inhibition of virus entry, are the most popular approaches in DR screenings. Cell-free systems and in vitro assays with purified proteins can be used; however, cellular assays with engineered cell lines, recombinant viruses and/or replicon systems, or pseudoviruses, are preferred as information on target modulation is obtained directly in a physiological environment. Compounds identified by mechanism-based assays in DR screenings against ZIKV, EBOV, and DNA viruses are described below. Although DR screenings based on mechanism-based assays could be more convenient (because the target is known), sometimes false positives can be identified. Other limits are the possible toxicity of the hits due to off-target effects and missing antiviral compounds acting by different mechanisms because the antiviral activity is restricted to a single process established a priori. In the following sections we describe the most recent advances of repurposing of existing and candidate drugs to treat infections caused by both RNA and DNA viruses (Table 3). Priority has been given to drugs that showed efficacy in clinical trials, or in animal models, and to investigational drugs exhibiting effective concentrations compatible with clinically achievable plasma levels in humans.Table 3Approved and Candidate Drugs with Repurposing Potential as Antiviral AgentsCompoundStatus/indicationVirusExperimental modelaThe most advanced phase of drug development is reported.TargetRefsMycophenolic acidApproved/immunomodulatorZIKVInfected cells in vitroNDbND: not determined.8Barrows N.J. et al.A screen of FDA-approved drugs for inhibitors of Zika virus infection.Cell Host Microbe. 2016; 20: 259-270Abstract Full Text Full Text PDF PubMed Scopus (393) Google ScholarDaptomycinApproved/antibacterialZIKVInfected cells in vitroND8Barrows N.J. et al.A screen of FDA-approved drugs for inhibitors of Zika virus infection.Cell Host Microbe. 2016; 20: 259-270Abstract Full Text Full Text PDF PubMed Scopus (393) Google ScholarNiclosamideApproved/antiparasiticZIKVInfected cells in vitroND andNS2B/NS3 protease9Xu M. et al.Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.Nat. Med. 2016; 22: 1101-1107Crossref PubMed Scopus (532) Google Scholar, 12Li Z. et al.Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction.Cell Res. 2017; 27: 1046-1064Crossref PubMed Scopus (148) Google ScholarAzithromycinApproved/antibacterialZIKVInfected cells in vitroND10Retallack H. et al.Zika virus cell tropism in the developing human brain and inhibition by azithromycin.Proc. Natl. Acad. Sci. U. S. A. 2016; 113: 14408-14413Crossref PubMed Scopus (367) Google ScholarNovobiocinApproved/antibacterialZIKVInfected cell lines in vitro, mouse modelNS2B/NS3 protease11Yuan S. et al.Structure-based discovery of clinically approved drugs as Zika virus NS2B-NS3 protease inhibitors that potently inhibit Zika virus infection invitro and invivo.Antiviral Res. 2017; 145: 33-43Crossref PubMed Scopus (105) Google ScholarNanchangmycinInvestigationalZIKVInfected cells in vitro, mouse neuron–glia ex vivo culturesVirus entry13Rausch K. et al.Screening bioactives reveals nanchangmycin as a broad spectrum antiviral active against Zika virus.Cell Rep. 2017; 18: 804-815Abstract Full Text Full Text PDF PubMed Scopus (135) Google ScholarHippeastrine hydrobromideInvestigationalZIKVInfected cells in vitro, organoids, mouse modelND14Zhou T. et al.High-content screening in hPSC-neural progenitors identifies drug candidates that inhibit Zika virus infection in fetal-like organoids and adult brain.Cell Stem Cell. 2017; 21: 274-283Abstract Full Text Full Text PDF PubMed Scopus (180) Google ScholarSofosbuvirApproved/antiviralZIKVInfected cells in vitro, mouse modelNS5 RNA polymerase15Bullard-Feibelman K.M. et al.The FDA-approved drug sofosbuvir inhibits Zika virus infection.Antiviral Res. 2017; 137: 134-140Crossref PubMed Scopus (207) Google Scholar, 19Mesci P. et al.Blocking Zika virus vertical transmission.Sci. Rep. 2018; 81218Crossref PubMed Scopus (49) Google Scholar, 20Sacramento C.Q. et al.The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication.Sci. Rep. 2017; 740920Crossref PubMed Scopus (169) Google ScholarRibavirinApproved/antiviralZIKVInfected cells in vitro, mouse modelNS5 RNA polymerase17Kamiyama N. et al.Ribavirin inhibits Zika virus (ZIKV) replication in vitro and suppresses viremia in ZIKV-infected STAT1-deficient mice.Antiviral Res. 2017; 146: 1-11Crossref PubMed Scopus (77) Google ScholarChloroquineApproved/antimalarialZIKVInfected cells in vitro, mouse model of vertical transmissionND22Delvecchio R. et al.Chloroquine, an endocytosis blocking agent, inhibits Zika virus infection in different cell models.Viruses. 2016; 8: 322Crossref PubMed Scopus (221) Google Scholar, 23Shiryaev S.A. et al.Repurposing of the anti-malaria drug chloroquine for Zika virus treatment and prophylaxis.Sci. Rep. 2017; 715771Crossref PubMed Scopus (105) Google ScholarMERS- and SARS-CoVInfected cells in vitroND47de Wilde A.H. et al.Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture.Antimicrob. Agents Chemother. 2014; 58: 4875-4884Crossref PubMed Scopus (581) Google ScholarMemantineApproved/treatment of Alzheimer's diseaseZIKVPrimary neurons in vitro, mouse modelND24Costa V.V. et al.N-Methyl-d-aspartate (NMDA) receptor blockade prevents neuronal death induced by Zika virus infection.mBio. 2017; 8e00350-17Crossref PubMed Scopus (67) Google ScholarProchlorperazineApproved/antiemeticDENVInfected cells in vitro, mouse modelEntry28Simanjuntak Y. et al.Repurposing of prochlorperazine for use against dengue virus infection.J. Infect. Dis. 2015; 211: 394-404Crossref PubMed Scopus (57) Google ScholarChlorcyclizineApproved/antihistamineHCVChimeric mouse modelEntry?29He S. et al.Repurposing of the antihistamine chlorcyclizine and related compounds for treatment of hepatitis C virus infection.Sci. Transl. Med. 2015; 7282ra249Crossref Scopus (117) Google ScholarManidipineApproved/antihypertensiveJEVZIKVInfected cells in vitro, mouse modelNS4B25Wang S. et al.Screening of FDA-approved drugs for inhibitors of Japanese encephalitis virus infection.J. Virol. 2017; 91e01055-17Crossref PubMed Scopus (91) Google ScholarHCMVInfected cells in vitroIE268Mercorelli B. et al.Repurposing the clinically approved calcium antagonist manidipine dihydrochloride as a new early inhibitor of human cytomegalovirus targeting the Immediate-Early 2 (IE2) protein.Antiviral Res. 2017; 150: 130-136Crossref PubMed Scopus (21) Google ScholarFavipiravirApproved/antiviralEBOVPhase 2 clinical trialRNA polymerase L33Sissoko D. et al.Experimental treatment with favipiravir for Ebola virus disease (the JIKI trial): a historically controlled, single-arm proof-of-concept trial in Guinea.PLoS Med. 2016; 13e1001967Crossref PubMed Scopus (402) Google ScholarGS-5734Investigational/antiviralMERS- and SARS-CoVNonhuman primatesRNA polymerase34Warren T.K. et al.Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys.Nature. 2016; 531: 381-385Crossref PubMed Scopus (1142) Google Scholar, 35Sheahan T.P. et al.Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses.Sci. Transl. Med. 2017; 9eaal3653Crossref PubMed Scopus (1197) Google ScholarImatinibApproved/anticancerMERS- and SARS-CoVInfected cells in vitroViral fusion3Coleman C.M. et al.Abelson kinase inhibitors are potent inhibitors of severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus fusion.J. Virol. 2016; 90: 8924-8933Crossref PubMed Scopus (217) Google ScholarChlorpromazineApproved/antipsychoticMERS- and SARS-CoVInfected cells in vitroND46Dyall J. et al.Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection.Antimicrob. Agents Chemother. 2014; 58: 4885-4893Crossref PubMed Scopus (516) Google Scholar, 47de Wilde A.H. et al.Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture.Antimicrob. Agents Chemother. 2014; 58: 4875-4884Crossref PubMed Scopus (581) Google ScholarChlarithromycin/Naproxen + OseltamivirApproved/antibacterial, anti-inflammatory (+antiviral)InfluenzaPhase 2b/3 clinical trialsND56Hung I.F.N. et al.Efficacy of clarithromycin-naproxen-oseltamivir combination in the treatment of patients hospitalized for influenza A(H3N2) infection: an open-label randomized, controlled, phase IIb/III trial.Chest. 2017; 151: 1069-1080Abstract Full Text Full Text PDF PubMed Scopus (89) Google ScholarNitazoxanideApproved/antiparasiticInfluenzaPhase 3 clinical trialsMaturation of hemagglutinin60McKimm-Breschkin J.L. et al.Prevention and treatment of respiratory viral infections: Presentations on antivirals, traditional therapies and host-directed interventions at the 5th ISIRV Antiviral Group conference.Antiviral Res. 2018; 149: 118-142Crossref PubMed Scopus (63) Google ScholarRotavirusPhase 2 clinical trialsViral morphogenesiswww.clinicaltrials.gov/ct2/show/NCT01328925NorovirusPhase 2 clinical trialsNDwww.clinicaltrials.gov/ct2/show/NCT03395405RaltegravirApproved/antiviralHerpesvirusInfected cells in vitroTerminase70Yan Z. et al.HIV integrase inhibitors block replication of alpha-, beta-, and gammaherpesviruses.mBio. 2014; 5e01318-01314Crossref Scopus (30) Google ScholarLopinavir/ritonavir + interferon β-1bApproved/antiviralMERS-CoVNonhuman primates, phase 2/3 clinical trialProtease50Chan J.F.W. et al.Treatment with lopinavir/ritonavir or interferon-beta1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset.J. Infect. Dis. 2015; 212: 1904-1913Crossref PubMed Scopus (546) Google Scholar, 51Arabi Y.M. et al.Treatment of Middle East respiratory syndrome with a combination of lopinavir-ritonavir and interferon-β1b (MIRACLE trial): study protocol for a randomized controlled trial.Trials. 2018; 19: 81Crossref PubMed Scopus (221) Google ScholarLopinavir/ritonavirHPVProof-of-concept clinical trialOverexpression RNAse L and?72Hampson L. et al.A single-arm, proof-of-concept trial of lopimune (lopinavir/ritonavir) as a treatment for HPV-related pre-invasive cervical disease.PLoS One. 2016; 11e0147917Crossref PubMed Scopus (25) Google Scholara The most advanced phase of drug development is reported.b ND: not determined. Open table in a new tab ZIKV is an arbovirus that recently caused a large outbreak in Latin America. Generally, ZIKV causes a self-limit