Document Report Card

ID: ALA1135407

Journal: J Med Chem

Title: Structure-based design of a parallel synthetic array directed toward the discovery of irreversible inhibitors of human rhinovirus 3C protease.

Authors: Johnson TO, Hua Y, Luu HT, Brown EL, Chan F, Chu SS, Dragovich PS, Eastman BW, Ferre RA, Fuhrman SA, Hendrickson TF, Maldonado FC, Matthews DA, Meador JW, Patick AK, Reich SH, Skalitzky DJ, Worland ST, Yang M, Zalman LS.

Abstract: Utilizing the tools of parallel synthesis and structure-based design, a new class of Michael acceptor-containing, irreversible inhibitors of human rhinovirus 3C protease (HRV 3CP) was discovered. These inhibitors are shown to inhibit HRV-14 3CP with rates of inactivation ranging from 886 to 31 400 M(-1) sec(-1). These inhibitors exhibit antiviral activity when tested against HRV-14 infected H1-HeLa cells, with EC(50) values ranging from 1.94 to 0.15 microM. No cytotoxicity was observed at the limits of the assay concentration. A crystal structure of one of the more potent inhibitors covalently bound to HRV-2 3CP is detailed. These compounds were also tested against HRV serotypes other than type 14 and were found to have highly variable activities.

CiteXplore: 11985469

DOI: 10.1021/jm010435c