Inhibitors of Cathepsin L Prevent Severe Acute Respiratory Syndrome Coronavirus Entry

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 33; pp. 11876 - 11881
• Main Authors: Simmons, Graham, Gosalia, Dhaval N., Rennekamp, Andrew J., Reeves, Jacqueline D., Diamond, Scott L., Bates, Paul, Varmus, Harold E.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 16.08.2005; National Acad Sciences
• Subjects: Biological Sciences; Cathepsin L; Cathepsins - antagonists & inhibitors; Cathepsins - metabolism; Cell Line; Cell lines; Cell Membrane - chemistry; Cell Membrane - drug effects; Cell Membrane - metabolism; Chlorides; Cysteine Endopeptidases - metabolism; Glycoproteins; Humans; Infections; Inhibitor drugs; Membrane Fusion - drug effects; Membrane Fusion - physiology; Microbiology; Molecular Structure; Protease Inhibitors - pharmacology; Quaternary ammonium compounds; Receptors; SARS coronavirus; SARS virus; SARS Virus - drug effects; SARS Virus - physiology; Severe acute respiratory syndrome; Severe Acute Respiratory Syndrome - enzymology; Severe Acute Respiratory Syndrome - prevention & control; Severe Acute Respiratory Syndrome - virology; Temperature; Vero cells; Virions; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0505577102

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.