3CLpro Inhibitor binding model
3CLpro Inhibitor Development

The SARS coronavirus is a positive-strand RNA virus.   The 5’ two-thirds of the genome encodes two overlapping ppolyproteins, pp1a and pp1ab, which are processed to generate the viral replication complex. During viral replication, the replicase polyprotein undergoes extensive processing by two viral proteases namely, chymotripsin-like protease (3CLpro) and papain-like protease (PLpro).  Because of their essential roles in viral replication, both proteases are recognized as attractive targets for development of anti-SARS therapeutics.  The structure and activity of active sites of both SARS-CoV 3CLpro and SARS-CoV PLpro have been elucidated.  Thus far, inhibitor design efforts are mostly limited to SARS-CoV 3CLpro and numerous covalent and noncovalent inhibitors have been reported.  In our continuing interest in the design and development of SARS-CoV 3CLpro inhibitors, we recently reported structure-based design of a number of potent peptidomimetic SARS-CoV 3CLpro inhibitors, described in initial papers below.


A.K. Ghosh, G. Gong, V. Grum-Tokars, D.C. Mulhearn, M. Coughlin, B.S. Prabhakar, K. Sleeman, S.C. Baker, M.E. Johnson, and A.D. Mesecar (2008) “Design, Synthesis and Antiviral Efficacy of a Series of Potent Chloropyridyl Ester-derived SARS-CoV 3CLpro Inhibitors,  Bioorganic & Medicinal Chemistry Letters, 18(20), 5684-5688. (Abstract)

A.K. Ghosh, K. Xi, V. Grum-Tokars, X. Xua, K. Ratia, W. Fu, K.V. Houser, S.C. Baker, M.E. Johnson and A.D. Mesecar (2007) “Structure-based design, synthesis, and biological evaluation of peptidomimetic SARS-CoV 3CLpro inhibitors”, Bioorg. Med. Chem. Lett. 17(21), 5876-5880. (Abstract)

A.K. Ghosh, K. Xi, M.E. Johnson, Susan C. Baker and A.D. Mesecar (2006) Progress in Anti-SARS Coronavirus Chemistry, Biology and Chemotherapy,” Ann. Reports Med. Chem., 41, 183-196. (Abstract)

A.K. Ghosh, K. Xi, K. Ratia, B.D. Santarsiero, W.T. Fu, B. Harcourt, P. Rota, S. Baker, M.E. Johnson, and A.D. Mesecar (2005) “Design and Synthesis of Peptidomimetic Severe Acute Respiratory Syndrome Chymotrypsin-like Protease Inhibitors,” Journal of Medicinal Chemistry, 48(22), 6767-6771. (Abstract)