Structure-Based Design of a Small Molecule CD4-Antagonist with Broad Spectrum Anti-HIV‑1 Activity

Earlier
we reported the discovery and design of NBD-556 and their
analogs which demonstrated their potential as HIV-1 entry inhibitors.
However, progress in developing these inhibitors has been stymied
by their CD4-agonist properties, an unfavorable trait for use as drug.
Here, we demonstrate the successful conversion of a full CD4-agonist
(NBD-556) through a partial CD4-agonist (NBD-09027), to a full CD4-antagonist
(NBD-11021) by structure-based modification of the critical oxalamide
midregion, previously thought to be intolerant of modification. NBD-11021
showed unprecedented neutralization breath for this class of inhibitors,
with pan-neutralization against a panel of 56 Env-pseudotyped HIV-1
representing diverse subtypes of clinical isolates (IC50 as low as 270 nM). The cocrystal structure of NBD-11021 complexed
to a monomeric HIV-1 gp120 core revealed its detail binding characteristics.
The study is expected to provide a framework for further development
of NBD series as HIV-1 entry inhibitors for clinical application against
AIDS.