A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals

Laura Riva; Shuofeng Yuan; Xin Yin; Laura Martin-Sancho; Naoko Matsunaga; Sebastian Burgstaller-Muehlbacher; Lars Pache; Paul P. De Jesus; Mitchell V. Hull; Max Chang; Jasper Fuk-Woo Chan; Jianli Cao; Vincent Kwok-Man Poon; Kristina Herbert; Tu-Trinh Nguyen; Yuan Pu; Courtney Nguyen; Andrey Rubanov; Luis Martinez-Sobrido; Wen-Chun Liu; Lisa Miorin; Kris M. White; Jeffrey R. Johnson; Christopher Benner; Ren Sun; Peter G. Schultz; Andrew Su; Adolfo Garcia-Sastre; Arnab K. Chatterjee; Kwok-Yung Yuen; Sumit K. Chanda

The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.16.044016 doi: bioRxiv preprint clinical candidates can identify additional unanticipated therapeutic options with accelerated evaluation for the treatment of COVID-19 disease. Here, we describe a high-throughput repositioning screen using the commercial library of 1,280 pharmacologically active compounds LOPAC®1280 and the ReFRAME (Repurposing, Focused Rescue, and Accelerated Medchem) drug collection, a comprehensive openaccess library of ~12,000 clinical-staged or approved small molecules respectively, to identify existing drugs that harbor antiviral activity against SARS-CoV-2 in a cell-based assay 27, 28 . The ReFRAME library has previously been used to successfully identify the anti-inflammatory auranofin as a potential therapy for tuberculosis 29 , the approved drug clofazimine as a potent antiparasitic compound that is now being tested for efficacy against Cryptosporidium 30 , and has also been used to identify and optimize the FDAapproved antifungal drug itraconazole as a novel efficacious molecule suitable for chronic administration as an anti-fibrotic 31 . Importantly, the ReFRAME library is unique in that it is the only repurposing collection we are aware of where nearly 50% of the library was derived from custom synthesis, as commercially available sources of these clinical molecules were not available 32 . Each of the molecules in this collection has been previously optimized for efficacy, safety, and bioavailability. Therefore, this enables leveraging of the considerable investment in research and development to compress the timeline required for drug discovery and development 33 . For example, repositioning is estimated to reduce the typical 10-17 year development process to 3-12 years 34 , and under emergency use authorization (EUA) for chemical, biological, radiological, and nuclear (CBRN) threats during public health emergencies, such as the SARS-CoV-2 pandemic, this may be abbreviated to a <6-month time frame.