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

Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry.

Author information

  • 1Department of Microbiology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. gsimmons@mail.med.upenn.edu

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.

PMID:
16081529
[PubMed - indexed for MEDLINE]
PMCID:
PMC1188015
Free PMC Article

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