Advocacy of targeting protease-activated receptors in severe coronavirus disease 2019

Br J Pharmacol. 2022 May;179(10):2086-2099. doi: 10.1111/bph.15587. Epub 2021 Jul 7.

Abstract

Identifying drug targets mitigating vascular dysfunction, thrombo-inflammation and thromboembolic complications in COVID-19 is essential. COVID-19 coagulopathy differs from sepsis coagulopathy. Factors that drive severe lung pathology and coagulation abnormalities in COVID-19 are not understood. Protein-protein interaction studies indicate that the tagged viral bait protein ORF9c directly interacts with PAR2, which modulates host cell IFN and inflammatory cytokines. In addition to direct interaction of SARS-CoV-2 viral protein with PARs, we speculate that activation of PAR by proteases plays a role in COVID-19-induced hyperinflammation. In COVID-19-associated coagulopathy elevated levels of activated coagulation proteases may cleave PARs in association with TMPRSS2. PARs activation enhances the release of cytokines, chemokines and tissue factor expression to propagate IFN-dependent inflammation, leukocyte-endothelial interaction, vascular permeability and coagulation responses. This hypothesis, corroborated by in vitro findings and emerging clinical evidence, will focus targeted studies of PAR1/2 blockers as adjuvant drugs against cytokine release syndrome and COVID-19-associated coagulopathy. LINKED ARTICLES: This article is part of a themed issue on The second wave: are we any closer to efficacious pharmacotherapy for COVID 19? (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.10/issuetoc.

Keywords: COVID-19-associated coagulopathy; PAR1; PAR2; acute respiratory distress syndrome; sepsis.

Publication types

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

MeSH terms

  • COVID-19 Drug Treatment*
  • Cytokine Release Syndrome / drug therapy
  • Humans
  • Inflammation
  • Receptors, Proteinase-Activated
  • SARS-CoV-2

Substances

  • Receptors, Proteinase-Activated