Synthesis and Evaluation of Keto-Glutamine Analogues as Potent Inhibitors of Severe Acute Respiratory Syndrome 3CLpro
Journal of Medicinal Chemistry2004Vol. 47(25), pp. 6113–6116
Citations Over TimeTop 10% of 2004 papers
Rajendra P. Jain, Hanna Pettersson, Jianmin Zhang, Katherine H. Aull, Pascal D. Fortin, Carly Huitema, Lindsay D. Eltis, Jonathan C. Parrish, Michael N.G. James, David S. Wishart, John C. Vederas
Abstract
The 3C-like proteinase (3CL(pro)) of severe acute respiratory syndrome (SARS) coronavirus is a key target for structure-based drug design against this viral infection. The enzyme recognizes peptide substrates with a glutamine residue at the P1 site. A series of keto-glutamine analogues with a phthalhydrazido group at the alpha-position were synthesized and tested as reversible inhibitiors against SARS 3CL(pro). Attachment of tripeptide (Ac-Val-Thr-Leu) to these glutamine-based "warheads" generated significantly better inhibitors (4a-c, 8a-d) with IC(50) values ranging from 0.60 to 70 microM.
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