DNA-encoded chemistry technology yields expedient access to SARS-CoV-2 M pro inhibitors

Proc Natl Acad Sci U S A. 2021 Sep 7;118(36):e2111172118. doi: 10.1073/pnas.2111172118.


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 [K i] = 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 (K i = 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 (K i = 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.

Keywords: antiviral; covalent inhibitors; drug discovery.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • COVID-19 / drug therapy
  • COVID-19 / virology
  • Cells, Cultured
  • Coronavirus 3C Proteases / antagonists & inhibitors*
  • Coronavirus 3C Proteases / genetics*
  • Coronavirus 3C Proteases / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery / methods*
  • Enzyme Activation
  • Genetic Engineering
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology*
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / genetics*
  • SARS-CoV-2 / metabolism
  • Structure-Activity Relationship
  • Virus Replication


  • Protease Inhibitors
  • Coronavirus 3C Proteases