DNA-encoded chemistry technology yields expedient access to SARS-CoV-2 Mpro inhibitors
In: Proceedings of the National Academy of Sciences of the United States of America, Jg. 118 (2021-09-07), Heft 36
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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.
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DNA-encoded chemistry technology yields expedient access to SARS-CoV-2 Mpro inhibitors
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Autor/in / Beteiligte Person: | 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 |
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Zeitschrift: | Proceedings of the National Academy of Sciences of the United States of America, Jg. 118 (2021-09-07), Heft 36 |
Veröffentlichung: | eScholarship, University of California, 2021 |
Medientyp: | academicJournal |
Umfang: | e2111172118 |
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