Antiviral agents targeted to interact with viral capsid proteins and a possible application to human immunodeficiency virus.
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 thereby 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, which inhibits disassembly. The hydrophobic pocket may be an essential functional component of the protein and, therefore, 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 for other proteins involved in cell metabolism, this class of antiviral agents is 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 will, therefore, depend on designing compounds that can enter and fit snugly into the hydrophobic pocket of a particular viral capsid protein. The major capsid protein, p24, of human immunodeficiency virus would be a likely suitable target.
D000998:Antiviral Agents / Q000494:pharmacology*; D002213:Capsid / Q000187:drug effects*; D006678:HIV / Q000187:drug effects*; D016655:HIV Core Protein p24; D007555:Isoxazoles / Q000494:pharmacology; D008958:Models, Molecular; D010849:Picornaviridae / Q000187:drug effects / Q000648:ultrastructure; D011487:Protein Conformation; D012191:Retroviridae Proteins; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D016655:HIV Core Protein p24; D007555:Isoxazoles; D012191:Retroviridae Proteins; C045978:disoxaril