Background:  High rates of therapeutic failure demands novel compounds aiming at new targets with superior pharmacokinetic/safety profiles. BMS-488043 (043) is an orally available HIV-1 Attachment inhibitor that was optimized through SAR to exhibit potent and selective antiviral activity along with superior pharmacokinetic properties to the prototype compound in this series, BMS-378806.

Methods:  Cell based and biochemical assays were used to determine the potency, cytotoxicity and inhibition mechanism of 043.

Results:  In vitro susceptibility assays indicate that 043 is effective against both M- and T-tropic HIV-1 laboratory strains, with potent activity against subtype B clinical isolates (median EC50 of 37 nM). It is inactive against HIV-2, other RNA viruses, and is non-cytotoxic against multiple cell lines. Gel filtration and Biocore biosensor analyses showed that 043 binds directly to gp120.  The binding was reversible and had a binding constant of 29 nM.  To characterize the resistance profile of 043, T-tropic HIV-1 strains (LAI and NL4-3) were passaged in vitro in the presence of increasing concentrations of 043. Genotypic analysis of the envelope gene of the emerging resistant viruses revealed amino acid substitutions that were predominantly located within the envelope protein gp120 (V68A, M426L, M434I, S440R, and M475I).  Substitutions M426L or M475I, which reside at or near CD4 contact points, conferred high levels of resistance.  They also decreased binding of 043 to gp120 by >/=100-fold, but did not affect gp120/CD4 interactions. A CD4 contact site mutation, W427V, which eliminated CD4/gp120 binding, also eliminated the binding of 043 to gp120. In addition, S375W that locates deep in the CD4-phe43 binding cavity and stabilizes gp120 binding to CD4, diminished binding to 043. Therefore, 043 binds to gp120 at a specific region that overlaps with that of CD4.

Conclusios:  BMS-488043 is a potent and selective HIV-1 inhibitor and member of the novel Attachment class of inhibitors that target gp120.  Its combination of novel mechanism, potency and favorable pharmacokinetic properties warrants further study.

Keywords: Entry Inhibitor; Attachment Inhibitor; New Antiretroviral Agent