title: The prototype HIV-1 maturation inhibitor, bevirimat, binds to the CA-SP1 cleavage site in immature Gag particles.
abstract: BACKGROUND
  Bevirimat, the prototype Human Immunodeficiency Virus type 1 (HIV-1) maturation inhibitor, is highly potent in cell culture and efficacious in HIV-1 infected patients. In contrast to inhibitors that target the active site of the viral protease, bevirimat specifically inhibits a single cleavage event, the final processing step for the Gag precursor where p25 (CA-SP1) is cleaved to p24 (CA) and SP1.
  
  
  RESULTS
  In this study, photoaffinity analogs of bevirimat and mass spectrometry were employed to map the binding site of bevirimat to Gag within immature virus-like particles. Bevirimat analogs were found to crosslink to sequences overlapping, or proximal to, the CA-SP1 cleavage site, consistent with previous biochemical data on the effect of bevirimat on Gag processing and with genetic data from resistance mutations, in a region predicted by NMR and mutational studies to have α-helical character. Unexpectedly, a second region of interaction was found within the Major Homology Region (MHR). Extensive prior genetic evidence suggests that the MHR is critical for virus assembly.
  
  
  CONCLUSIONS
  This is the first demonstration of a direct interaction between the maturation inhibitor, bevirimat, and its target, Gag. Information gained from this study sheds light on the mechanisms by which the virus develops resistance to this class of drug and may aid in the design of next-generation maturation inhibitors.
authors.affiliation: Department of Microbiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA. gillian-air@ouhsc.edu
authors.forename: Albert T
authors.initials: AT
authors.lastname: Nguyen
authors.forename: Christa L
authors.initials: CL
authors.lastname: Feasley
authors.forename: Ken W
authors.initials: KW
authors.lastname: Jackson
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Nitz
authors.forename: Karl
authors.initials: K
authors.lastname: Salzwedel
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Air
authors.forename: Michael
authors.initials: M
authors.lastname: Sakalian
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D057809:HEK293 Cells; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D011485:Protein Binding; D013386:Succinates / Q000494:pharmacology*; D014315:Triterpenes / Q000494:pharmacology*; D019065:Virus Assembly / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors / Q000378:metabolism; D053978:Pentacyclic Triterpenes
chemical_list: D019380:Anti-HIV Agents; D013386:Succinates; D014315:Triterpenes; D054301:gag Gene Products, Human Immunodeficiency Virus; C059827:HIV gag protein p25; C479935:bevirimat; D053978:Pentacyclic Triterpenes