Why All the Fury over Furin?

J Med Chem. 2022 Feb 24;65(4):2747-2784. doi: 10.1021/acs.jmedchem.1c00518. Epub 2021 Aug 2.

Abstract

Analysis of the SARS-CoV-2 sequence revealed a multibasic furin cleavage site at the S1/S2 boundary of the spike protein distinguishing this virus from SARS-CoV. Furin, the best-characterized member of the mammalian proprotein convertases, is an ubiquitously expressed single pass type 1 transmembrane protein. Cleavage of SARS-CoV-2 spike protein by furin promotes viral entry into lung cells. While furin knockout is embryonically lethal, its knockout in differentiated somatic cells is not, thus furin provides an exciting therapeutic target for viral pathogens including SARS-CoV-2 and bacterial infections. Several peptide-based and small-molecule inhibitors of furin have been recently reported, and select cocrystal structures have been solved, paving the way for further optimization and selection of clinical candidates. This perspective highlights furin structure, substrates, recent inhibitors, and crystal structures with emphasis on furin's role in SARS-CoV-2 infection, where the current data strongly suggest its inhibition as a promising therapeutic intervention for SARS-CoV-2.

Publication types

  • Review

MeSH terms

  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • COVID-19 / metabolism
  • COVID-19 Drug Treatment
  • Furin / antagonists & inhibitors*
  • Furin / metabolism
  • Humans
  • Peptides / chemistry
  • Peptides / pharmacology*
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Spike Glycoprotein, Coronavirus / antagonists & inhibitors*
  • Spike Glycoprotein, Coronavirus / metabolism

Substances

  • Antiviral Agents
  • Peptides
  • Small Molecule Libraries
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • FURIN protein, human
  • Furin