DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors
In: Communications Chemistry, Jg. 6 (2023-08-01), Heft 1
Online
academicJournal
- 164
The development of SARS-CoV-2 main protease (Mpro) inhibitors for the treatment of COVID-19 has mostly benefitted from X-ray structures and preexisting knowledge of inhibitors; however, an efficient method to generate Mpro inhibitors, which circumvents such information would be advantageous. As an alternative approach, we show here that DNA-encoded chemistry technology (DEC-Tec) can be used to discover inhibitors of Mpro. An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using Mpro as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of Mpro with low nanomolar Ki values. Furthermore, these compounds demonstrate efficacy against mutant forms of Mpro that have shown resistance to the standard-of-care drug nirmatrelvir. Overall, this work demonstrates that DEC-Tec can efficiently generate novel and potent inhibitors without preliminary chemical or structural information.
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DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors
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Autor/in / Beteiligte Person: | Jimmidi, Ravikumar ; Chamakuri, Srinivas ; Lu, Shuo ; Ucisik, Melek Nihan ; Chen, Peng-Jen ; Bohren, Kurt M ; Moghadasi, Seyed Arad ; Versteeg, Leroy ; Nnabuife, Christina ; Li, Jian-Yuan ; Qin, Xuan ; Chen, Ying-Chu ; Faver, John C ; Nyshadham, Pranavanand ; Sharma, Kiran L ; Sankaran, Banumathi ; Judge, Allison ; Yu, Zhifeng ; Li, Feng ; Pollet, Jeroen ; Harris, Reuben S ; Matzuk, Martin M ; Palzkill, Timothy ; Young, Damian W |
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Zeitschrift: | Communications Chemistry, Jg. 6 (2023-08-01), Heft 1 |
Veröffentlichung: | eScholarship, University of California, 2023 |
Medientyp: | academicJournal |
Umfang: | 164 |
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