학술논문
DNA-encoded chemistry technology yields expedient access to SARS-CoV-2 Mpro inhibitors
Document Type
article
Author
Chamakuri, Srinivas; Lu, Shuo; Ucisik, Melek Nihan; Bohren, Kurt M; Chen, Ying-Chu; Du, Huang-Chi; Faver, John C; Jimmidi, Ravikumar; Li, Feng; Li, Jian-Yuan; Nyshadham, Pranavanand; Palmer, Stephen S; Pollet, Jeroen; Qin, Xuan; Ronca, Shannon E; Sankaran, Banumathi; Sharma, Kiran L; Tan, Zhi; Versteeg, Leroy; Yu, Zhifeng; Matzuk, Martin M; Palzkill, Timothy; Young, Damian W
Source
Proceedings of the National Academy of Sciences of the United States of America. 118(36)
Subject
Language
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration-approved drug-like molecule to impede the COVID-19 pandemic. The sluggish pace of traditional therapeutic discovery is poorly suited to producing targeted treatments against rapidly evolving viruses. Here, we used an affinity-based screen of 4 billion DNA-encoded molecules en masse to identify a potent class of virus-specific inhibitors of the SARS-CoV-2 main protease (Mpro) without extensive and time-consuming medicinal chemistry. CDD-1714, the initial three-building-block screening hit (molecular weight [MW] = 542.5 g/mol), was a potent inhibitor (inhibition constant [Ki] = 20 nM). CDD-1713, a smaller two-building-block analog (MW = 353.3 g/mol) of CDD-1714, is a reversible covalent inhibitor of Mpro (Ki = 45 nM) that binds in the protease pocket, has specificity over human proteases, and shows in vitro efficacy in a SARS-CoV-2 infectivity model. Subsequently, key regions of CDD-1713 that were necessary for inhibitory activity were identified and a potent (Ki = 37 nM), smaller (MW = 323.4 g/mol), and metabolically more stable analog (CDD-1976) was generated. Thus, screening of DNA-encoded chemical libraries can accelerate the discovery of efficacious drug-like inhibitors of emerging viral disease targets.