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

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.

The PI3K/Akt/mTOR pathway: A potential pharmacological target in COVID-19

“… [30] Another retrospective cohort study reported a reduction in 30-day mortality after SARS-CoV-2 infection in nursing-home residents taking metformin-containing diabetes regimens. [31] These clinical findings are in line with data from Duarte and collaborators, [32] who found, via computational analysis, that metformin can reverse the transcriptional signature induced by SARS-CoV-2 in vitro . [32] A case of complete recovery from COVID-19 in a recipient of a kidney-pancreas transplant who continued baseline immunosuppression with everolimus has also been reported.…”

“… [31] These clinical findings are in line with data from Duarte and collaborators, [32] who found, via computational analysis, that metformin can reverse the transcriptional signature induced by SARS-CoV-2 in vitro . [32] A case of complete recovery from COVID-19 in a recipient of a kidney-pancreas transplant who continued baseline immunosuppression with everolimus has also been reported. [33] Considering the positive outcome despite the presence of risk factors for severe COVID-19, the potential beneficial role of immunosuppression in this condition was highlighted.…”

The neutralization effect of montelukast on SARS-CoV-2 is shown by multiscale in silico simulations and combined in vitro studies

“…A similar virtual drug repurposing approach was applied against SARS-CoV-2 targets when the COVID19 pandemic began, and montelukast was found to be a promising molecule in both the Mpro and the spike/ACE2 interface. Although there are many extensive and ongoing research studies to identify small therapeutics against COVID-19, [28][29][30] no effective small molecule-based therapy has yet been found. Therefore, the findings of this study may contribute to the discovery of new solutions for the treatment of this disease.…”

Organoid Studies in COVID-19 Research

“…There are multiple reports on COVID-19 research in human PSC-derived lung organoids that cover various topics: cell tropism, host cell responses, genetic variation influencing virus susceptibility, novel drug candidates, and impact of the environment ( 23 - 28 ). Studies by Pei et al ( 24 ) and Tiwari et al ( 26 ) have demonstrated that SARS-CoV-2 can infect human PSC-derived lung organoids and that they are susceptible to SARS-CoV-2 infection and replication because they highly express ACE2 and TMPRSS2, which are both critical for viral entry.…”

“…These were then validated in human AdSC-derived lung organoids, which exhibited suppressed viral replication upon Lapatinib treatment. Duarte and colleagues ( 23 ) have reported another screening of FDA-approved drugs using a similar strategy. The authors started from available large-scale data sets and identified candidates that might potentially affect COVID-19, based on gene expression profiles.…”