C-2 Thiophenyl Tryptophan Trimers Inhibit Cellular Entry of SARS-CoV-2 through Interaction with the Viral Spike (S) Protein

J Med Chem. 2023 Aug 10;66(15):10432-10457. doi: 10.1021/acs.jmedchem.3c00576. Epub 2023 Jul 20.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, by infecting cells via the interaction of its spike protein (S) with the primary cell receptor angiotensin-converting enzyme (ACE2). To search for inhibitors of this key step in viral infection, we screened an in-house library of multivalent tryptophan derivatives. Using VSV-S pseudoparticles, we identified compound 2 as a potent entry inhibitor lacking cellular toxicity. Chemical optimization of 2 rendered compounds 63 and 65, which also potently inhibited genuine SARS-CoV-2 cell entry. Thermofluor and microscale thermophoresis studies revealed their binding to S and to its isolated receptor binding domain (RBD), interfering with the interaction with ACE2. High-resolution cryoelectron microscopy structure of S, free or bound to 2, shed light on cell entry inhibition mechanisms by these compounds. Overall, this work identifies and characterizes a new class of SARS-CoV-2 entry inhibitors with clear potential for preventing and/or fighting COVID-19.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2 / chemistry
  • COVID-19*
  • Cryoelectron Microscopy
  • Humans
  • Protein Binding
  • SARS-CoV-2* / metabolism
  • Spike Glycoprotein, Coronavirus / metabolism
  • Tryptophan / metabolism
  • Tryptophan / pharmacology

Substances

  • Tryptophan
  • Angiotensin-Converting Enzyme 2
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2