title: The structure of antiviral agents that inhibit uncoating when complexed with viral capsids.
abstract: The tertiary structure of most icosahedral viral capsid proteins consists of an eight-stranded antiparallel beta-barrel with a hydrophobic interior. In a group of picornaviruses, this hydrophobic pocket can be filled by suitable organic molecules, which stop viral uncoating after attachment and penetration into the host cell. The antiviral activity of these agents is probably due to increased rigidity of the capsid protein, thereby inhibiting disassembly. The hydrophobic pocket may be an essential functional component of the protein and may have been conserved in the evolution of many viruses from a common precursor. Since eight-stranded anti-parallel beta-barrels, with a topology as in viral capsid proteins, are not generally found in other proteins involved in cell metabolism, antiviral agents that bind in the interior of viral capsid proteins are likely to be more virus-specific and less cytotoxic. Furthermore, the greatest conservation of viral capsid proteins occurs within this pocket, whereas the least conserved part is the antigenic exterior. Thus, compounds that bind to such a pocket are likely to be effective against a broader group of serologically distinct viruses. Discovery of antiviral agents of this type depends on designing compounds that can enter and fit snugly into the hydrophobic pocket of a particular viral capsid protein.
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, Indiana.
authors.forename: M G
authors.initials: MG
authors.lastname: Rossmann
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology; D002213:Capsid / Q000378:metabolism* / Q000648:ultrastructure; D003461:Crystallography; D004352:Drug Resistance, Microbial / Q000235:genetics; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D012229:Rhinovirus / Q000187:drug effects* / Q000648:ultrastructure; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents