Cell Type-Specific Anti-Viral Effects of Novel SARS-CoV-2 Main Protease Inhibitors

Int J Mol Sci. 2023 Feb 16;24(4):3972. doi: 10.3390/ijms24043972.

Abstract

Recently, we have described novel pyridyl indole esters and peptidomimetics as potent inhibitors of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) main protease. Here, we analysed the impact of these compounds on viral replication. It has been shown that some antivirals against SARS-CoV-2 act in a cell line-specific way. Thus, the compounds were tested in Vero, Huh-7, and Calu-3 cells. We showed that the protease inhibitors at 30 µM suppress viral replication by up to 5 orders of magnitude in Huh-7 cells, while in Calu-3 cells, suppression by 2 orders of magnitude was achieved. Three pyridin-3-yl indole-carboxylates inhibited viral replication in all cell lines, indicating that they might repress viral replication in human tissue as well. Thus, we investigated three compounds in human precision-cut lung slices and observed donor-dependent antiviral activity in this patient-near system. Our results provide evidence that even direct-acting antivirals may act in a cell line-specific manner.

Keywords: SARS-CoV-2; azapeptide nitriles; cell line specificity pyridyl indole carboxylates; peptidomimetics; protease inhibitors.

MeSH terms

  • Antiviral Agents / pharmacology
  • COVID-19*
  • Hepatitis C, Chronic*
  • Humans
  • Indoles / pharmacology
  • Protease Inhibitors / pharmacology
  • SARS-CoV-2

Substances

  • Antiviral Agents
  • 3C-like proteinase, SARS-CoV-2
  • Protease Inhibitors
  • Indoles

Grants and funding

M.G. and C.E.M. were supported by the Volkswagen Foundation (9A894). This publication was supported by the Open Access Publication Fund of the University of Würzburg.