DNA-Encoded Chemistry Technology Yields Expedient Access to SARS-CoV-2M Pro Inhibitors

Authors

Srinivas Chamakuri
Shuo Lu
Melek Nihan Ucisik
Kurt M Bohren
Ying-Chu Chen
Huang-Chi Du
John C Faver
Ravikumar Jimmidi
Feng Li
Jian-Yuan Li
Pranavanand Nyshadham
Stephen S Palmer
Jeroen Pollet
Xuan Qin
Shannon E Ronca
Banumathi Sankaran
Kiran L Sharma
Zhi Tan
Leroy Versteeg
Zhifeng Yu
Martin M Matzuk
Timothy Palzkill
Damian W Young

Publication Date

9-7-2021

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2111172118

PMID

34426525

PMCID

PMC8433497

PubMedCentral® Posted Date

8-23-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, COVID-19, Cells, Cultured, Coronavirus 3C Proteases, Dose-Response Relationship, Drug, Drug Discovery, Enzyme Activation, Genetic Engineering, Humans, Models, Molecular, Molecular Conformation, Molecular Structure, Protease Inhibitors, SARS-CoV-2, Structure-Activity Relationship, Virus Replication, COVID-19 Drug Treatment, antiviral, drug discovery, covalent inhibitors

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.

Comments

Associated Data