Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing.
Riva, Laura; Yuan, Shuofeng; Yin, Xin; Martin-Sancho, Laura; Matsunaga, Naoko; Pache, Lars; Burgstaller-Muehlbacher, Sebastian; De Jesus, Paul D; Teriete, Peter; Hull, Mitchell V; Chang, Max W; Chan, Jasper Fuk-Woo; Cao, Jianli; Poon, Vincent Kwok-Man; Herbert, Kristina M; Cheng, Kuoyuan; Nguyen, Tu-Trinh H; Rubanov, Andrey; Pu, Yuan; Nguyen, Courtney; Choi, Angela; Rathnasinghe, Raveen; Schotsaert, Michael; Miorin, Lisa; Dejosez, Marion; Zwaka, Thomas P; Sit, Ko-Yung; Martinez-Sobrido, Luis; Liu, Wen-Chun; White, Kris M; Chapman, Mackenzie E; Lendy, Emma K; Glynne, Richard J; Albrecht, Randy; Ruppin, Eytan; Mesecar, Andrew D; Johnson, Jeffrey R; Benner, Christopher; Sun, Ren; Schultz, Peter G; Su, Andrew I; García-Sastre, Adolfo; Chatterjee, Arnab K; Yuen, Kwok-Yung; Chanda, Sumit K.
Riva L; Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Yuan S; State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
Yin X; Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
Martin-Sancho L; Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
Matsunaga N; Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Pache L; Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Burgstaller-Muehlbacher S; Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
De Jesus PD; Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Teriete P; Center for Integrative Bioinformatics Vienna, Max Perutz Laboratories, University of Vienna and Medical University of Vienna, Vienna, Austria.
Hull MV; Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Chang MW; Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Chan JF; Calibr at Scripps Research, La Jolla, CA, USA.
Cao J; Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
Poon VK; State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
Herbert KM; Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
Cheng K; Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
Nguyen TH; State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
Rubanov A; Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
Pu Y; Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
Nguyen C; State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
Choi A; Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
Rathnasinghe R; Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
Schotsaert M; Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Miorin L; Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD, USA.
Dejosez M; Biological Sciences Graduate Program, University of Maryland, College Park, MD, USA.
Zwaka TP; Calibr at Scripps Research, La Jolla, CA, USA.
Sit KY; Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Martinez-Sobrido L; Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Liu WC; Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
White KM; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Chapman ME; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Lendy EK; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Glynne RJ; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Albrecht R; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Ruppin E; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Mesecar AD; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Johnson JR; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Benner C; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Sun R; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Schultz PG; Huffington Foundation Center for Cell-based Research in Parkinson's Disease, Department for Cell, Regenerative and Developmental Biology, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Su AI; Huffington Foundation Center for Cell-based Research in Parkinson's Disease, Department for Cell, Regenerative and Developmental Biology, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
García-Sastre A; Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
Chatterjee AK; Texas Biomedical Research Institute, San Antonio, TX, USA.
Yuen KY; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Chanda SK; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nature ; 586(7827): 113-119, 2020 10.
Article in English | MEDLINE | ID: covidwho-672174
Semantic information from SemMedBD (by NLM)
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The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of the severe pneumonia-like disease coronavirus disease 2019 (COVID-19)1. The development of a vaccine is likely to take at least 12-18 months, and the typical timeline for approval of a new antiviral therapeutic agent can exceed 10 years. Thus, repurposing of known drugs could substantially accelerate the deployment of new therapies for COVID-19. Here we profiled a library of drugs encompassing approximately 12,000 clinical-stage or Food and Drug Administration (FDA)-approved small molecules to identify candidate therapeutic drugs for COVID-19. We report the identification of 100 molecules that inhibit viral replication of SARS-CoV-2, including 21 drugs that exhibit dose-response relationships. Of these, thirteen were found to harbour effective concentrations commensurate with probable achievable therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod2-4 and the cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825 and ONO 5334. Notably, MDL-28170, ONO 5334 and apilimod were found to antagonize viral replication in human pneumocyte-like cells derived from induced pluripotent stem cells, and apilimod also demonstrated antiviral efficacy in a primary human lung explant model. Since most of the molecules identified in this study have already advanced into the clinic, their known pharmacological and human safety profiles will enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19.
Antiviral Agents/analysis; Antiviral Agents/pharmacology; Betacoronavirus/drug effects; Coronavirus Infections/drug therapy; Coronavirus Infections/virology; Drug Evaluation, Preclinical; Drug Repositioning; Pneumonia, Viral/drug therapy; Pneumonia, Viral/virology; Adenosine Monophosphate/analogs & derivatives; Adenosine Monophosphate/pharmacology; Alanine/analogs & derivatives; Alanine/pharmacology; Alveolar Epithelial Cells/cytology; Alveolar Epithelial Cells/drug effects; Betacoronavirus/growth & development; COVID-19; Cell Line; Cysteine Proteinase Inhibitors/analysis; Cysteine Proteinase Inhibitors/pharmacology; Dose-Response Relationship, Drug; Drug Synergism; Gene Expression Regulation/drug effects; Humans; Hydrazones; Induced Pluripotent Stem Cells/cytology; Models, Biological; Morpholines/analysis; Morpholines/pharmacology; Pandemics; Pyrimidines; Reproducibility of Results; SARS-CoV-2; Small Molecule Libraries/analysis; Small Molecule Libraries/pharmacology; Triazines/analysis; Triazines/pharmacology; Virus Internalization/drug effects; Virus Replication/drug effects
https://dx.doi.org/10.1038/s41586-020-2577-1
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pneumonia, Viral / Coronavirus Infections / Drug Evaluation, Preclinical / Drug Repositioning / Betacoronavirus Type of study: Experimental Studies / Prognostic study Topics: Traditional medicine / Vaccines Language: English Journal: Nature Year: 2020 Document Type: Article Affiliation country: S41586-020-2577-1