Identifying FDA-approved drugs with multimodal properties against COVID-19 using a data-driven approach and a lung organoid model of SARS-CoV-2 entry

Molecular Medicine

Shuibing Chen¹  Yuling Han¹  Yaron Bram²  Robert E. Schwartz²  Rodrigo R. R. Duarte³  Douglas F. Nixon³  Timothy R. Powell³  Dennis C. Copertino³  Luis P. Iñiguez³  Jez L. Marston³ 

[1] Department of Surgery, Weill Cornell Medicine, Cornell University;Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, Cornell University;Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, Cornell University;

关键词: Drug repositioning;    Lung organoids;    Pandemic;    COVID-19;    Connectivity mapping;    Chemoinformatics;   

DOI  :  10.1186/s10020-021-00356-6

来源: DOAJ

【 摘 要 】

Abstract Background Vaccination programs have been launched worldwide to halt the spread of COVID-19. However, the identification of existing, safe compounds with combined treatment and prophylactic properties would be beneficial to individuals who are waiting to be vaccinated, particularly in less economically developed countries, where vaccine availability may be initially limited. Methods We used a data-driven approach, combining results from the screening of a large transcriptomic database (L1000) and molecular docking analyses, with in vitro tests using a lung organoid model of SARS-CoV-2 entry, to identify drugs with putative multimodal properties against COVID-19. Results Out of thousands of FDA-approved drugs considered, we observed that atorvastatin was the most promising candidate, as its effects negatively correlated with the transcriptional changes associated with infection. Atorvastatin was further predicted to bind to SARS-CoV-2’s main protease and RNA-dependent RNA polymerase, and was shown to inhibit viral entry in our lung organoid model. Conclusions Small clinical studies reported that general statin use, and specifically, atorvastatin use, are associated with protective effects against COVID-19. Our study corroborrates these findings and supports the investigation of atorvastatin in larger clinical studies. Ultimately, our framework demonstrates one promising way to fast-track the identification of compounds for COVID-19, which could similarly be applied when tackling future pandemics.

【 授权许可】

Unknown