Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry

Proc Natl Acad Sci U S A. 2005 Aug 16;102(33):11876-81. doi: 10.1073/pnas.0505577102. Epub 2005 Aug 4.

Abstract

Severe acute respiratory syndrome (SARS) is caused by an emergent coronavirus (SARS-CoV), for which there is currently no effective treatment. SARS-CoV mediates receptor binding and entry by its spike (S) glycoprotein, and infection is sensitive to lysosomotropic agents that perturb endosomal pH. We demonstrate here that the lysosomotropic-agent-mediated block to SARS-CoV infection is overcome by protease treatment of target-cell-associated virus. In addition, SARS-CoV infection was blocked by specific inhibitors of the pH-sensitive endosomal protease cathepsin L. A cell-free membrane-fusion system demonstrates that engagement of receptor followed by proteolysis is required for SARS-CoV membrane fusion and indicates that cathepsin L is sufficient to activate membrane fusion by SARS-CoV S. These results suggest that SARS-CoV infection results from a unique, three-step process: receptor binding and induced conformational changes in S glycoprotein followed by cathepsin L proteolysis within endosomes. The requirement for cathepsin L proteolysis identifies a previously uncharacterized class of inhibitor for SARS-CoV infection.

Publication types

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

MeSH terms

  • Cathepsin L
  • Cathepsins / antagonists & inhibitors*
  • Cathepsins / metabolism
  • Cell Line
  • Cell Membrane / chemistry
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cysteine Endopeptidases / metabolism
  • Humans
  • Membrane Fusion / drug effects
  • Membrane Fusion / physiology
  • Molecular Structure
  • Protease Inhibitors / pharmacology*
  • SARS Virus / drug effects*
  • SARS Virus / physiology*
  • Severe Acute Respiratory Syndrome / enzymology
  • Severe Acute Respiratory Syndrome / prevention & control*
  • Severe Acute Respiratory Syndrome / virology*
  • Temperature

Substances

  • Protease Inhibitors
  • Cathepsins
  • Cysteine Endopeptidases
  • CTSL protein, human
  • Cathepsin L