Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry

Proceedings of the National Academy of Sciences of the United States of America
Graham SimmonsPaul Bates

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.

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Jul 10, 2003·Proceedings of the National Academy of Sciences of the United States of America·Dhaval N Gosalia, Scott L Diamond
Mar 11, 2004·Proceedings of the National Academy of Sciences of the United States of America·Graham SimmonsPaul Bates
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Citations

Oct 27, 2010·Immunology and Cell Biology·Christopher E AndoniouMariapia A Degli-Esposti
Feb 10, 2009·Nature Reviews. Microbiology·Lanying DuShibo Jiang
Jul 4, 2008·Nature Structural & Molecular Biology·Stephen C Harrison
May 24, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Tommy AlainPeter A Forsyth
May 21, 2008·Proceedings of the National Academy of Sciences of the United States of America·Shiori HagaYukihito Ishizaka
Mar 27, 2009·Proceedings of the National Academy of Sciences of the United States of America·Sandrine BelouzardGary R Whittaker
Jan 16, 2010·The Journal of Biological Chemistry·Slavko ČeruNataša Kopitar-Jerala
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May 27, 2011·Journal of Virology·Kazuya ShiratoFumihiro Taguchi
Jul 13, 2007·Journal of Virology·Patricia EifartAndreas Herrmann
Sep 4, 2009·Journal of Virology·Marceline CôtéShan-Lu Liu
Jul 31, 2009·Journal of Virology·Elizabeth M JohnsonTerence S Dermody
Oct 12, 2007·Journal of Virology·Rachel L KaletskyPaul Bates
Nov 3, 2006·Journal of Virology·Yingyun CaiXuming Zhang
Dec 7, 2007·Journal of Virology·Melinda A Brindley, Wendy Maury

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