STRUCTURES OF POLIOVIRUS COMPLEXES WITH ANTIVIRAL DRUGS - IMPLICATIONS FOR VIRAL STABILITY AND DRUG DESIGN

Background: Picornaviruses, such as the structurally related polioviru ses and rhinoviruses, are important human pathogens which have been th e target of major drug development efforts. Receptor-mediated uncoatin g and thermal inactivation of poliovirus and rhinovirus are inhibited by agents that bind to each virus by inserting into a pocket in the be ta barrel of the viral capsid protein, VP1. This pocket, which is norm ally empty in human rhinovirus-14 (HRV14), is occupied by an unknown n atural ligand in poliovirus. Structural studies of HRV14-drug complexe s have shown that drug binding causes large, localized changes in the conformation of VP1. Results: We report the crystal structures of six complexes between poliovirus and capsid-binding, antiviral drugs, incl uding complexes of four different drugs with the Sabin vaccine strain of type 3 poliovirus, and complexes of one of these drugs with two oth er poliovirus strains that contain sequence differences in the drug-bi nding site. In each complex, the changes in capsid structure associate d with drug binding are limited to minor adjustments in the conformati ons of a few side chains lining the binding site. Conclusions: The min or structural changes caused by drug binding suggest a model of drug a ction in which it is the conformational changes prevented by the bound drug, rather than obvious conformational changes induced by drug bind ing, which exert the biological effect. Our results, along with additi onal structures of rhinovirus-drug complexes, suggest possible improve ments in drug design, and provide important clues about the nature of the conformational changes that are involved in the uncoating process.