RESUMEN

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.

Asunto(s)

Antivirales/síntesis química , Inhibidores Enzimáticos/síntesis química , Rhinovirus/efectos de los fármacos , Proteínas Virales/antagonistas & inhibidores , Proteasas Virales 3C , Antivirales/química , Antivirales/farmacología , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Cisteína Endopeptidasas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Células HeLa , Humanos , Unión Proteica , Rhinovirus/química , Relación Estructura-Actividad