A screen of almost 12,000 clinical stage or US Food and Drug Administration (FDA) approved drugs identifies 13 compounds that inhibit replication of SARS-CoV-2 in cultured cells. A practical strategy for developing treatments for COVID-19 is the repurposing of drugs that have been approved or are under clinical investigation, as their pharmacological activities and safety profiles have already been established.
Sumit Chanda and colleagues describe a large-scale evaluation of nearly 12,000 drugs for their potential to block viral replication. The screen reveals 100 molecules that can inhibit viral replication, of which 13 show particularly promising characteristics – notably, being effective at realistic dose levels. These include an anti-HIV compound called R 82913, a member of a drug family used to treat diabetes (PPAR-γ agonists) named DS-6930, a potential drug for the treatment of osteoporosis (known as ONO 5334) and apilimod, a drug developed to treat autoimmune disorders such as Crohn’s disease.
Three of the most potent compounds – including ONO 5334, apilimod and MDL 28170, which has previously been shown to impair Ebola virus infection – were tested for their ability to reduce SARS-CoV-2 replication in cultured lung tissue. ONO 5334, MDL 28170 and apilimod were shown to reduce the number of infected cells by 72%, 65% and 85%, respectively. Apilimod has previously been found to be well-tolerated in humans, with a favourable safety profile at doses in a range likely to have an antiviral effect in patients.
Many of drugs identified in this study have been tested in clinical settings, which could enable accelerated preclinical and clinical evaluation of these drugs for the treatment of patients with COVID-19, the authors conclude.
Abstract
The emergence of the novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19)1. The development of a vaccine is likely to require at least 12-18 months, and the typical timeline for approval of a novel antiviral therapeutic can exceed 10 years. Thus, repurposing of known drugs could significantly accelerate the deployment of novel therapies for COVID-19. Towards this end, we profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules that inhibit viral replication, including 21 known drugs that exhibit dose response relationships. Of these, thirteen were found to harbor effective concentrations likely commensurate with 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 iPSC-derived pneumocyte-like cells, and the PIKfyve inhibitor 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, the known pharmacological and human safety profiles of these compounds will enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19.
Authors
Laura Riva, Shuofeng Yuan, Xin Yin, Laura Martin-Sancho, Naoko Matsunaga, Lars Pache, Sebastian Burgstaller-Muehlbacher, Paul D De Jesus,Peter Teriete, Mitchell V Hull, Max W Chang, Jasper Fuk-Woo Chan, Jianli Cao, Vincent Kwok-Man Poon, Kristina M. Herbert, Kuoyuan Cheng, Tu-Trinh H Nguyen, Andrey Rubanov, Yuan Pu, Courtney Nguyen, Angela Choi, Raveen Rathnasinghe, Michael Schotsaert, Lisa Miorin, Marion Dejosez, Thomas P Zwaka, Ko-Yung Sit, Luis Martinez-Sobrido, Wen-Chun Liu, Kris M White, Mackenzie E Chapman, Emma K Lendy, Richard J Glynne, Randy Albrecht, Eytan Ruppin, Andrew D Mesecar, Jeffrey R Johnson, Christopher Benner, Ren Sun,Peter G Schultz, Andrew I Su, Adolfo García-Sastre, Arnab K Chatterjee, Kwok-Yung Yuen, Sumit K Chanda
[link url="https://www.nature.com/articles/s41586-020-2577-1"]Nature abstract[/link]