Pharmacophore variants of the macrocyclic peptide triazole inactivator of HIV-1 Env

GUPTA, MONISHA; CANZIANI, GABRIELA; ANG, CHARLES; MOHAMMADI, MOHAMMADJAVAD; ABRAMS, CAMERON F.; YANG, DEREK; SMITH, AMOS B.; CHAIKEN, IRWIN

MEDICINAL CHEMISTRY RESEARCH

BIRKHAUSER BOSTON INC

Lugar: Boston, MA; Año: 2023 vol. 32 p. 1497 - 1509

1054-2523

Previously we established a family of macrocyclic peptide triazoles (cPTs) that inactivate the Env protein complex of HIV-1, and identified the pharmacophore that engages Env’s receptor binding pocket. Here, we examined the hypothesis that the side chains of both components of the triazole Pro - Trp segment of cPT pharmacophore work in tandem to make intimate contacts with two proximal subsites of the overall CD4 binding site of gp120 to stabilize binding and function. Variations of the triazole Pro R group, which previously had been significantly optimized, led to identification of a derivative, MG-II-20, containing a pyrazole substitution. MG-II-20 has improved functional properties over previously examined cPTs, with KD for gp120 in the nM range. In contrast, new modifications of the Trp indole side chain, with either methyl- or bromo- components appended, had disruptive effects on gp120 binding, reflecting the sensitivity of function to changes in this component of the encounter complex. Plausible in silico models of cPT:gp120 complex structures were obtained that are consistent with the overall hypothesis of occupancy by the triazole Pro and Trp side chains, respectively, into the β20/21 and Phe43 sub-cavities. The overall results strengthen the definition of the cPT-Env inactivator binding site and provide a new lead composition (MG-II-20) as well as structure-function findings to guide future HIV-1 Env inactivator design. Graphical Abstract: [Figure not available: see fulltext.]