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.

Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions

“…S14 and table S2). The potent small-molecule inhibitor of HIV-1 entry, BMS-626529 (40), also stabilized the low-FRET ground-state conformation for both HIV-1 JR-FL and HIV-1 NL4-3 to an extent comparable to the broadly neutralizing antibodies tested (Fig. 4, F and K).…”

“Cytoplasmic domain effects on exposure of co-receptor-binding sites of HIV-1 Env”

“…The co-receptor binding site is not well exposed on virions, even on those with CD4 independent Env proteins [15, 25]. To compare our results by using attachment inhibitors is difficult, because CD4-independent viruses and some HIV-1 envelopes (92UG046) can be resistant to entry inhibitors [16]. However, the present results clearly indicate that alteration of cytoplasmic tail length (FL, CT84, CT17) did not modulate co-receptor usage of WT or chimeric SF162 R5 or 92UG046 X4 Envs.…”

Pyrroloaryls and pyrroloheteroaryls: Inhibitors of the HIV fusion/attachment, reverse transcriptase and integrase

“…unlikely to promote resistance [52]. In continuous discoveries, a further derivatized class of pyrrolopyrimidinones (13) were discovered and checked for their in vitro anti-HIV attachment inhibitory potential, in which five to twenty fold increased potential was observed in addition to the seven-fold increase in exposure over BMS-488043 in a rat pharmacokinetic assay.…”