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

Yuling Han¹  Shuibing Chen¹  Yaron Bram²  Robert E. Schwartz³  Dennis C. Copertino⁴  Luis P. Iñiguez⁴  Jez L. Marston⁴  Douglas F. Nixon⁴  Rodrigo R. R. Duarte⁵  Timothy R. Powell⁵ 

[1] Department of Surgery, Weill Cornell Medicine, Cornell University, New York, NY, USA;Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA;Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA;Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, Cornell University, New York, NY, USA;Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, Cornell University, Belfer Research Building, 5th floor, 413 E. 69th St., 10021, New York, NY, USA;Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, Cornell University, Belfer Research Building, 5th floor, 413 E. 69th St., 10021, New York, NY, USA;Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK;

关键词: Drug repositioning;    Lung organoids;    Pandemic;    COVID-19;    Connectivity mapping;    Chemoinformatics;    Molecular docking;    Drug screening;    Drug testing;    Atorvastatin;   

DOI  :  10.1186/s10020-021-00356-6

来源: Springer

【 摘 要 】

BackgroundVaccination 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.MethodsWe 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.ResultsOut 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.ConclusionsSmall 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】

CC BY