Discovery and development of safe-in-man broad-spectrum antiviral agents

Viral diseases are the leading cause of morbidity and mortality in developing countries. Broad-spectrum antiviral agents (BSAA) are key players in control of viral diseases. Here, we reviewed the discovery and development process of BSAAs, focusing on compounds with available safety profiles in human. We summarized the information on approved, investigational and experimental safe-in-man BSAAs in freely accessible database at https://drugvirus.info/. The number of these BSAAs will be increased as well as their spectrum of indications will be expanded pending the results of further pre-clinical and clinical studies. This will ultimately reinforce the arsenal of available antiviral options and provide better protection of general population from emerging and re-emerging viral diseases.

[1]  Dayan Wang,et al.  Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals , 2013, Nature Communications.

[2]  M. Habjan,et al.  T7 RNA polymerase-dependent and -independent systems for cDNA-based rescue of Rift Valley fever virus. , 2008, The Journal of general virology.

[3]  J. Somberg,et al.  The Drug Development Process , 1988, Journal of clinical pharmacology.

[4]  G. Taylor.  Animal models of respiratory syncytial virus infection , 2017, Vaccine.

[5]  R. A. KtJNKLE,et al.  Infectious disease. , 2015, Clinical privilege white paper.

[6]  Chiou-Feng Lin,et al.  The antiparasitic drug niclosamide inhibits dengue virus infection by interfering with endosomal acidification independent of mTOR , 2018, PLoS neglected tropical diseases.

[7]  Ping Liu,et al.  25‐Hydroxycholesterol Protects Host against Zika Virus Infection and Its Associated Microcephaly in a Mouse Model , 2017, Immunity.

[8]  A. Fauci,et al.  Emerging Viral Diseases: Confronting Threats with New Technologies , 2014, Science Translational Medicine.

[9]  S. Polyak,et al.  Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses , 2019, Journal of Virology.

[10]  Y. Nishimura,et al.  Editorial: Drug Repositioning: Current Advances and Future Perspectives , 2018, Front. Pharmacol..

[11]  A. García-Sastre,et al.  Insertion of a GFP Reporter Gene in Influenza Virus , 2013, Current protocols in microbiology.

[12]  Gilles A. Spoden,et al.  Inhibition by Cellular Vacuolar ATPase Impairs Human Papillomavirus Uncoating and Infection , 2014, Antimicrobial Agents and Chemotherapy.

[13]  Yasuhiko Irie,et al.  Discovery and development of safe-in-man broad-spectrum antiviral agents , 2020, International Journal of Infectious Diseases.

[14]  A. Ghram,et al.  A multiplex real-time RT-PCR for simultaneous detection of four most common avian respiratory viruses. , 2018, Virology.

[15]  S. Polyak,et al.  The Antiviral Drug Arbidol Inhibits Zika Virus , 2018, Scientific Reports.

[16]  A. Hurt,et al.  Using the Ferret as an Animal Model for Investigating Influenza Antiviral Effectiveness , 2016, Front. Microbiol..

[17]  E. Gould,et al.  Lineage-Specific Real-Time RT-PCR for Yellow Fever Virus Outbreak Surveillance, Brazil , 2017, Emerging infectious diseases.

[18]  Dipali G Sashital.  Pathogen detection in the CRISPR–Cas era , 2018, Genome Medicine.

[19]  Jinming Li,et al.  The applications of CRISPR/Cas system in molecular detection , 2018, Journal of cellular and molecular medicine.

[20]  Carolina Q. Sacramento,et al.  The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication , 2017, Scientific Reports.

[21]  M. Ferrer,et al.  Efficacy and Mechanism of Action of Low Dose Emetine against Human Cytomegalovirus , 2016, PLoS pathogens.

[22]  Anton Simeonov,et al.  Drug repurposing screens and synergistic drug‐combinations for infectious diseases , 2017, British journal of pharmacology.

[23]  Eurosurveillance Editorial Team,et al.  Note from the editors: World Health Organization declares novel coronavirus (2019-nCoV) sixth public health emergency of international concern , 2020, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[24]  Neil Boonham,et al.  Methods in virus diagnostics: from ELISA to next generation sequencing. , 2014, Virus research.

[25]  K. Dooley,et al.  Importance of Drug Pharmacokinetics at the Site of Action , 2017, Clinical and translational science.

[26]  Ruili Huang,et al.  Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen , 2016, Nature Medicine.

[27]  M. Landry.  Nucleic acid hybridization in viral diagnosis. , 1990, Clinical biochemistry.

[28]  Marion P G Koopmans,et al.  Modeling rotavirus infection and antiviral therapy using primary intestinal organoids. , 2015, Antiviral research.

[29]  R. Padmanabhan,et al.  Amodiaquine, an antimalarial drug, inhibits dengue virus type 2 replication and infectivity , 2014, Antiviral Research.

[30]  Interferon-induced transmembrane protein-3 genetic variant rs12252 is associated with COVID-19 mortality , 2021, Genomics.

[31]  David S. Wishart,et al.  DrugBank 5.0: a major update to the DrugBank database for 2018 , 2017, Nucleic Acids Res..

[32]  S. Yoon,et al.  Efficient long-term amplification of hepatitis B virus isolates after infection of slow proliferating HepG2-NTCP cells. , 2019, Journal of hepatology.

[33]  H. Ellerbrok,et al.  A novel three‐dimensional cell culture method enhances antiviral drug screening in primary human cells , 2018, Antiviral research.

[34]  C. Verfaillie,et al.  Replication of the Zika virus in different iPSC-derived neuronal cells and implications to assess efficacy of antivirals. , 2017, Antiviral research.

[35]  Nikos Vasilakis,et al.  A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection. , 2016, Cell host & microbe.

[36]  Haniye Sadat Sajadi,et al.  Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017 , 2018, The Lancet.

[37]  G. Olinger,et al.  Testing therapeutics in cell-based assays: Factors that influence the apparent potency of drugs , 2018, PloS one.

[38]  Susumu Y. Imanishi,et al.  Phosphoproteomics to Characterize Host Response During Influenza A Virus Infection of Human Macrophages* , 2016, Molecular & Cellular Proteomics.

[39]  Břetislav Rada,et al.  ANTIVIRAL ACTION AND SELECTIVITY OF 6‐AZAURIDINE , 1977, Annals of the New York Academy of Sciences.

[40]  Tzong-Yuan Wu,et al.  Antiviral activities of niclosamide and nitazoxanide against chikungunya virus entry and transmission , 2016, Antiviral Research.

[41]  D. Hamasaki,et al.  The electroretinogram of the iguana and Tokay gecko. , 1967, Vision research.

[42]  Wei Zheng,et al.  Improving therapy of severe infections through drug repurposing of synergistic combinations. , 2019, Current opinion in pharmacology.

[43]  O. Vapalahti,et al.  Obatoclax, saliphenylhalamide and gemcitabine inhibit Zika virus infection in vitro and differentially affect cellular signaling, transcription and metabolism , 2017, Antiviral research.

[44]  T. Aittokallio,et al.  Novel activities of safe-in-human broad-spectrum antiviral agents , 2018, Antiviral Research.

[45]  H. Okano,et al.  Increased Cytotoxicity of Herpes Simplex Virus Thymidine Kinase Expression in Human Induced Pluripotent Stem Cells , 2019, International journal of molecular sciences.

[46]  M. Heise,et al.  Mutations in nsP1 and PE2 are critical determinants of Ross River virus-induced musculoskeletal inflammatory disease in a mouse model. , 2011, Virology.

[47]  Olive Lloyd-Baker.  IDENTIFICATION OF NOVEL , 1964 .

[48]  E. De Clercq,et al.  Broad-spectrum antiviral activity of the carbocyclic analog of 3-deazaadenosine. , 1983, Antiviral research.

[49]  K. Shimada,et al.  A New Fluoroquinolone Derivative Exhibits Inhibitory Activity against Human Immunodeficiency Virus Type 1 Replication , 1999, Chemotherapy.

[50]  Wenling Wang,et al.  High-Throughput Screening and Identification of Potent Broad-Spectrum Inhibitors of Coronaviruses , 2019, Journal of Virology.

[51]  S. Anders,et al.  JNJ872 inhibits influenza A virus replication without altering cellular antiviral responses. , 2016, Antiviral research.

[52]  R. Bartenschlager,et al.  A Novel Inhibitor IDPP Interferes with Entry and Egress of HCV by Targeting Glycoprotein E1 in a Genotype-Specific Manner , 2017, Scientific reports.

[53]  M. Peppelenbosch,et al.  6-Thioguanine inhibits rotavirus replication through suppression of Rac1 GDP/GTP cycling , 2018, Antiviral Research.

[54]  Katja Schenke-Layland,et al.  Self-Organized Cerebral Organoids with Human-Specific Features Predict Effective Drugs to Combat Zika Virus Infection. , 2017, Cell reports.

[55]  Yan Yuan,et al.  Niclosamide inhibits lytic replication of Epstein‐Barr virus by disrupting mTOR activation , 2017, Antiviral research.

[56]  S. Salinas,et al.  Zika virus induces strong inflammatory responses and impairs homeostasis and function of the human retinal pigment epithelium , 2018, EBioMedicine.

[57]  H. Katinger,et al.  Rescue of influenza virus expressing GFP from the NS1 reading frame. , 2004, Virology.

[58]  N. Shanks,et al.  Are animal models predictive for humans? , 2009, Philosophy, ethics, and humanities in medicine : PEHM.

[59]  T. Ahola,et al.  Versatile Trans-Replication Systems for Chikungunya Virus Allow Functional Analysis and Tagging of Every Replicase Protein , 2016, PloS one.

[60]  C. Cheng,et al.  Male germ cells support long-term propagation of Zika virus , 2018, Nature Communications.

[61]  R. K. Robins,et al.  Broad-Spectrum Antiviral Activity of Virazole: 1-f8- D-Ribofuranosyl- 1,2,4-triazole- 3-carboxamide , 1972, Science.

[62]  L. Delang,et al.  The future of antivirals: broad-spectrum inhibitors , 2015, Current opinion in infectious diseases.

[63]  Emily M. Lee,et al.  Emetine inhibits Zika and Ebola virus infections through two molecular mechanisms: inhibiting viral replication and decreasing viral entry , 2018, Cell Discovery.

[64]  M. Rosa-Calatrava,et al.  Drug Repurposing Approaches for the Treatment of Influenza Viral Infection: Reviving Old Drugs to Fight Against a Long-Lived Enemy , 2019, Front. Immunol..

[65]  D. Kaplan,et al.  Niclosamide rescues microcephaly in a humanized in vivo model of Zika infection using human induced neural stem cells , 2018, Biology Open.

[66]  T. Liang,et al.  Human stem cell-derived hepatocytes as a model for hepatitis B virus infection, spreading and virus-host interactions. , 2017, Journal of hepatology.

[67]  Z. Memish,et al.  The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health — The latest 2019 novel coronavirus outbreak in Wuhan, China , 2020, International Journal of Infectious Diseases.

[68]  Tudor I. Oprea,et al.  DrugCentral 2018: an update , 2018, Nucleic Acids Res..

[69]  Guangdi Li,et al.  Approved Antiviral Drugs over the Past 50 Years , 2016, Clinical Microbiology Reviews.

[70]  Haniye Sadat Sajadi,et al.  Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017 , 2018, The Lancet.

[71]  T. Tenson,et al.  Novel Antiviral Activities of Obatoclax, Emetine, Niclosamide, Brequinar, and Homoharringtonine , 2019, Viruses.

[72]  A. Osterhaus,et al.  An improved plaque reduction virus neutralization assay for human metapneumovirus. , 2007, Journal of virological methods.

[73]  J. Bartlett,et al.  Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[74]  A. Tanuri,et al.  Natural Plant Alkaloid (Emetine) Inhibits HIV-1 Replication by Interfering with Reverse Transcriptase Activity , 2015, Molecules.

[75]  D. Krysan,et al.  Repurposing Estrogen Receptor Antagonists for the Treatment of Infectious Disease , 2018, mBio.

[76]  Lisa E. Gralinski,et al.  Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses , 2017, Science Translational Medicine.

[77]  Qisheng Zhang,et al.  High-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain. , 2017, Cell stem cell.

[78]  L. Enquist,et al.  Retrograde axonal transport of rabies virus is unaffected by interferon treatment but blocked by emetine locally in axons , 2018, PLoS pathogens.

[79]  D. Smee,et al.  Methods for evaluation of antiviral efficacy against influenza virus infections in animal models. , 2013, Methods in molecular biology.

[80]  Evan Bolton,et al.  PubChem 2019 update: improved access to chemical data , 2018, Nucleic Acids Res..

[81]  C. Howard,et al.  Emerging virus diseases: can we ever expect the unexpected? , 2012, Emerging Microbes & Infections.

[82]  Mickael Guedj,et al.  Analysis of drug combinations: current methodological landscape , 2015, Pharmacology research & perspectives.

[83]  P. Sanseau,et al.  Drug repurposing: progress, challenges and recommendations , 2018, Nature Reviews Drug Discovery.

[84]  H. Bergmans,et al.  Animal models in virus research: their utility and limitations , 2013, Critical reviews in microbiology.

[85]  S. Parasuraman,et al.  Toxicological screening , 2011, Journal of pharmacology & pharmacotherapeutics.

[86]  T. Pan,et al.  Glycopeptide Antibiotics Potently Inhibit Cathepsin L in the Late Endosome/Lysosome and Block the Entry of Ebola Virus, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) , 2016, The Journal of Biological Chemistry.

[87]  Wu Zhong,et al.  Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro , 2020, Cell Research.

[88]  Sehee Park,et al.  Salinomycin Inhibits Influenza Virus Infection by Disrupting Endosomal Acidification and Viral Matrix Protein 2 Function , 2018, Journal of Virology.

[89]  Matt Carter.  Chapter 14 – Cell Culture Techniques , 2015 .

[90]  R. Schwendener,et al.  Niclosamide Is a Proton Carrier and Targets Acidic Endosomes with Broad Antiviral Effects , 2012, PLoS pathogens.

[91]  Y. Qiu,et al.  Zika virus infection induces RNAi-mediated antiviral immunity in human neural progenitors and brain organoids , 2019, Cell Research.

[92]  M. Diamond,et al.  Animal Models of Zika Virus Infection, Pathogenesis, and Immunity , 2017, Journal of Virology.

[93]  Liying Xing,et al.  Comparison of three quantification methods for the TZM-bl pseudovirus assay for screening of anti-HIV-1 agents. , 2016, Journal of virological methods.

[94]  J. Carette,et al.  A CRISPR toolbox to study virus–host interactions , 2017, Nature Reviews Microbiology.

[95]  L. R. Petersen,et al.  Zika Virus. , 2016, The New England journal of medicine.

[96]  R. Scheuermann,et al.  Virus Pathogen Database and Analysis Resource (ViPR): A Comprehensive Bioinformatics Database and Analysis Resource for the Coronavirus Research Community , 2012, Viruses.

[97]  Nicole M. Bouvier,et al.  Animal models for influenza virus pathogenesis, transmission, and immunology , 2014, Journal of Immunological Methods.

[98]  M. Bjørås,et al.  Expanding the activity spectrum of antiviral agents. , 2019, Drug discovery today.

[99]  V. Alabaster,et al.  The fall and rise of in vivo pharmacology. , 2002, Trends in pharmacological sciences.

[100]  H. Hsieh,et al.  Inhibition of Severe Acute Respiratory Syndrome Coronavirus Replication by Niclosamide , 2004, Antimicrobial Agents and Chemotherapy.

[101]  Manolis Kellis,et al.  Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells , 2014, Science.

[102]  M. Koopmans,et al.  Mycophenolic acid potently inhibits rotavirus infection with a high barrier to resistance development. , 2016, Antiviral research.

[103]  T. Aittokallio,et al.  Obatoclax, Saliphenylhalamide, and Gemcitabine Inhibit Influenza A Virus Infection* , 2012, The Journal of Biological Chemistry.

[104]  X. Saelens,et al.  The proton translocation domain of cellular vacuolar ATPase provides a target for the treatment of influenza A virus infections , 2011, British journal of pharmacology.

[105]  R. Angell,et al.  Identification of Broad-Spectrum Antiviral Compounds by Targeting Viral Entry , 2019, Viruses.

[106]  A. Iwasaki,et al.  Topical application of aminoglycoside antibiotics enhances host resistance to viral infections in a microbiota-independent manner , 2018, Nature Microbiology.

[107]  Douglas D Young,et al.  Small molecule modifiers of microRNA miR-122 function for the treatment of hepatitis C virus infection and hepatocellular carcinoma. , 2010, Journal of the American Chemical Society.

[108]  Max A. Horlbeck,et al.  Parallel shRNA and CRISPR-Cas9 screens enable antiviral drug target identification , 2016, Nature chemical biology.

[109]  Gregory Dolin,et al.  8U.S. Food and Drug Administration , 2016 .

[110]  V. Thiel,et al.  Research Models and Tools for the Identification of Antivirals and Therapeutics against Zika Virus Infection , 2018, Viruses.

[111]  S. Einav,et al.  Combating Intracellular Pathogens with Repurposed Host-Targeted Drugs , 2018, ACS infectious diseases.

[112]  David J Margolis,et al.  Key Concepts of Clinical Trials: A Narrative Review , 2011, Postgraduate medicine.

[113]  Jia Xu,et al.  Identification of Three Antiviral Inhibitors against Japanese Encephalitis Virus from Library of Pharmacologically Active Compounds 1280 , 2013, PloS one.

[114]  Beyond members of the Flaviviridae family, sofosbuvir also inhibits chikungunya virus replication , 2018 .

[115]  Raman Sharma,et al.  Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis C virus replication. , 2011, Journal of medicinal chemistry.

[116]  S. Cherry,et al.  Screening Bioactives Reveals Nanchangmycin as a Broad Spectrum Antiviral Active against Zika Virus. , 2017, Cell reports.

[117]  X. Montagutelli,et al.  Animal models are essential to biological research: issues and perspectives , 2015, Future science OA.

[118]  Hongmei Gao,et al.  Optimization and validation of the TZM-bl assay for standardized assessments of neutralizing antibodies against HIV-1. , 2014, Journal of immunological methods.

[119]  Giulio Superti-Furga,et al.  Common Nodes of Virus–Host Interaction Revealed Through an Integrated Network Analysis , 2019, Front. Immunol..

[120]  Michael A. Funk,et al.  Drug Repurposing , 2022, Drug Discovery.

[121]  T. Aittokallio,et al.  Antiviral Properties of Chemical Inhibitors of Cellular Anti-Apoptotic Bcl-2 Proteins , 2017, Viruses.

[122]  M. Heise,et al.  Animal Models of Chikungunya Virus Infection and Disease. , 2016, The Journal of infectious diseases.