TY - JOUR
T1 - 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
AU - Duarte, Rodrigo R R
AU - Copertino, Dennis
AU - Iñiguez, Luis
AU - Marston, Jez
AU - Bram, Yaron
AU - Han, Yuling
AU - Schwartz, Robert
AU - Chen, Shuibing
AU - Nixon, Douglas
AU - Powell, Timothy R
N1 - Funding Information:
This work was partly enabled by a grant from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES BEX1279/13-0) to RRRD. JLM was supported in part by a Medical Scientist Training Program grant to the Weill Cornell-Rockefeller-Sloan Kettering Tri-Institutional MD-PhD Program (T32GM007739).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/9/9
Y1 - 2021/9/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85114664492&partnerID=8YFLogxK
U2 - 10.1186/s10020-021-00356-6
DO - 10.1186/s10020-021-00356-6
M3 - Article
SN - 1076-1551
VL - 27
JO - Molecular Medicine
JF - Molecular Medicine
IS - 1
M1 - 105
ER -
