title: Activity of the HIV-1 attachment inhibitor BMS-626529, the active component of the prodrug BMS-663068, against CD4-independent viruses and HIV-1 envelopes resistant to other entry inhibitors.
abstract: BMS-626529 is a novel small-molecule HIV-1 attachment inhibitor active against both CCR5- and CXCR4-tropic viruses. BMS-626529 functions by preventing gp120 from binding to CD4. A prodrug of this compound, BMS-663068, is currently in clinical development. As a theoretical resistance pathway to BMS-663068 could be the development of a CD4-independent phenotype, we examined the activity of BMS-626529 against CD4-independent viruses and investigated whether resistance to BMS-626529 could be associated with a CD4-independent phenotype. Finally, we evaluated whether cross-resistance exists between BMS-626529 and other HIV-1 entry inhibitors. Two laboratory-derived envelopes with a CD4-independent phenotype (one CXCR4 tropic and one CCR5 tropic), five envelopes from clinical isolates with preexisting BMS-626529 resistance, and several site-specific mutant BMS-626529-resistant envelopes were examined for their dependence on CD4 for infectivity or susceptibility to BMS-626529. Viruses resistant to other entry inhibitors (enfuvirtide, maraviroc, and ibalizumab) were also examined for susceptibility to BMS-626529. Both CD4-independent laboratory isolates retained sensitivity to BMS-626529 in CD4(-) cells, while HIV-1 envelopes from viruses resistant to BMS-626529 exhibited no evidence of a CD4-independent phenotype. BMS-626529 also exhibited inhibitory activity against ibalizumab- and enfuvirtide-resistant envelopes. While there appeared to be some association between maraviroc resistance and reduced susceptibility to BMS-626529, an absolute correlation cannot be presumed, since some CCR5-tropic maraviroc-resistant envelopes remained sensitive to BMS-626529. Clinical use of the prodrug BMS-663068 is unlikely to promote resistance via generation of CD4-independent virus. No cross-resistance between BMS-626529 and other HIV entry inhibitors was observed, which could allow for sequential or concurrent use with different classes of entry inhibitors.
authors.affiliation: Bristol-Myers Squibb, Research and Development, Wallingford, Connecticut, USA.
authors.forename: Zhufang
authors.initials: Z
authors.lastname: Li
authors.forename: Nannan
authors.initials: N
authors.lastname: Zhou
authors.forename: Yongnian
authors.initials: Y
authors.lastname: Sun
authors.forename: Neelanjana
authors.initials: N
authors.lastname: Ray
authors.forename: Max
authors.initials: M
authors.lastname: Lataillade
authors.forename: George J
authors.initials: GJ
authors.lastname: Hanna
authors.forename: Mark
authors.initials: M
authors.lastname: Krystal
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens / Q000378:metabolism; D003510:Cyclohexanes / Q000494:pharmacology; D024882:Drug Resistance, Viral / Q000187:drug effects; D000077560:Enfuvirtide; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D000077592:Maraviroc; D010755:Organophosphates / Q000378:metabolism / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011991:Receptors, Virus / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; C584152:BMS-626529; D065100:CCR5 Receptor Antagonists; C584933:CCR5 protein, human; D015704:CD4 Antigens; C527276:CXCR4 protein, human; D003510:Cyclohexanes; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D010755:Organophosphates; D010446:Peptide Fragments; D010879:Piperazines; D011355:Prodrugs; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D011991:Receptors, Virus; D014230:Triazoles; D000077560:Enfuvirtide; C576364:fostemsavir; C481504:ibalizumab; D000077592:Maraviroc