STRUCTURE OF POLIOVIRUS/ANTIVIRAL DRUG COMPLEXES

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A number of antiviral drugs have been shown to bind to enteroviruses (e.g. polio- and coxsackieviruses) and rhinoviruses and to inhibit their infectivity by preventing conformational changes required for cell attachment and entry. These drugs are of considerable medical and economic significance for prophylaxis of rhinovirus induced common cold (which account for 80% of the colds in the United States) and for early intervention in poliomyelitis and coxsackievirus induced diseases. We propose a series of crystallographic studies of complexes of several antiviral drugs with poliovirus. The goals of these studies will be twofold: 1) to provide a basis for the rational design of new antivirals with improved activity or altered specificities among the entero and rhino- viruses, and 2) to probe the factors controlling the conformational rearrangements associated with cell attachment and cell entry. The crystallographic studies will include complexes of antiviral agents made by Janssen Pharmaceutica and by Sterling-Winthrop with the Sabin strain of type 3 and the Mahoney strain of type 1 poliovirus. The crystallographic studies will also include the structures of drug resistant variants (which will be selected and sequenced by Roland Rueckert at the University of Wisconsin). The structures of the complexes will be compared with the structures of complexes of similar agents with rhinovirus 14 and rhinovirus 1a (currently being studied by Rossmann et al. at Purdue University). The information gained from the structures will be used to design and synthesize compounds with altered activities and specificities (in collaboration with Janssen Pharmaceutica and with K.C. Nicolau at RISC).