Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing.
Laura RivaShuofeng YuanXin YinLaura Martin-SanchoNaoko MatsunagaLars PacheSebastian Burgstaller-MuehlbacherPaul D De JesusPeter TerieteMitchell V HullMax W ChangJasper Fuk-Woo ChanJianli CaoVincent Kwok-Man PoonKristina M HerbertKuoyuan ChengTu-Trinh H NguyenAndrey RubanovYuan PuCourtney NguyenAngela ChoiRaveen RathnasingheMichael SchotsaertLisa MiorinMarion DejosezThomas P ZwakaKo-Yung SitLuis Martinez-SobridoWen-Chun LiuKris M WhiteMackenzie E ChapmanEmma K LendyRichard J GlynneRandy A AlbrechtEytan RuppinAndrew D MesecarJeffrey R JohnsonChristopher BennerRen SunPeter G SchultzAndrew I SuAdolfo García-SastreArnab K ChatterjeeKwok-Yung YuenSumit K ChandaPublished in: Nature (2020)
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.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- coronavirus disease
- induced pluripotent stem cells
- drug administration
- endothelial cells
- end stage renal disease
- drug induced
- primary care
- newly diagnosed
- chronic kidney disease
- ejection fraction
- intensive care unit
- small molecule
- cell therapy
- mesenchymal stem cells
- high throughput
- peritoneal dialysis
- climate change
- prognostic factors
- patient reported outcomes