title: Localized changes in the gp120 envelope glycoprotein confer resistance to human immunodeficiency virus entry inhibitors BMS-806 and #155.
abstract: BMS-806 and the related compound, #155, are novel inhibitors of human immunodeficiency virus type 1 (HIV-1) entry that bind the gp120 exterior envelope glycoprotein. BMS-806 and #155 block conformational changes in the HIV-1 envelope glycoproteins that are induced by binding to the host cell receptor, CD4. We tested a panel of HIV-1 envelope glycoprotein mutants and identified several that were resistant to the antiviral effects of BMS-806 and #155. In the CD4-bound conformation of gp120, the amino acid residues implicated in BMS-806 and #155 resistance line the "phenylalanine 43 cavity" and a water-filled channel that extends from this cavity to the inner domain. Structural considerations suggest a model in which BMS-806 and #155 bind gp120 prior to receptor binding and, upon CD4 binding, are accommodated in the Phe-43 cavity and adjacent channel. The integrity of the nearby V1/V2 variable loops and N-linked carbohydrates on the V1/V2 stem indirectly influences sensitivity to the drugs. A putative binding site for BMS-806 and #155 between the gp120 receptor-binding regions and the inner domain, which is thought to interact with the gp41 transmembrane envelope glycoprotein, helps to explain the mode of action of these drugs.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute. Department of Pathology and Division of AIDS, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Navid
authors.initials: N
authors.lastname: Madani
authors.forename: Ana Luisa
authors.initials: AL
authors.lastname: Perdigoto
authors.forename: Kumar
authors.initials: K
authors.lastname: Srinivasan
authors.forename: Jason M
authors.initials: JM
authors.lastname: Cox
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Chruma
authors.forename: Judith
authors.initials: J
authors.lastname: LaLonde
authors.forename: Martha
authors.initials: M
authors.lastname: Head
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Sodroski
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D004285:Dogs; D024882:Drug Resistance, Viral / Q000235:genetics; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D010649:Phenylalanine / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D017434:Protein Structure, Tertiary
chemical_list: D019380:Anti-HIV Agents; C477855:BMS-378806; D015699:HIV Envelope Protein gp120; D010879:Piperazines; D010649:Phenylalanine