4RZ8

Crystal structure of HIV-1 gp120 core in complex with NBD-11021, a small molecule CD4-antagonist

Summary for 4RZ8

• Entry DOI: 10.2210/pdb4rz8/pdb
• Descriptor: Envelope glycoprotein gp120, 2-acetamido-2-deoxy-beta-D-glucopyranose, 5-(4-chlorophenyl)-N-{(S)-[5-(hydroxymethyl)-4-methyl-1,3-thiazol-2-yl][(2R)-piperidin-2-yl]methyl}-1H-pyrrole-2-carboxamide, ... (5 entities in total)
• Functional Keywords: hiv-1 gp120, nbd-11021, small molecule cd4-antagonist, phe 43 cavity, viral protein
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 4
• Total formula weight: 168222.92

Authors

Kwon, Y.D.,Debnath, A.K.,Kwong, P.D. (deposition date: 2014-12-18, release date: 2015-09-09, Last modification date: 2024-10-16)

Primary citation

Curreli, F.,Kwon, Y.D.,Zhang, H.,Scacalossi, D.,Belov, D.S.,Tikhonov, A.A.,Andreev, I.A.,Altieri, A.,Kurkin, A.V.,Kwong, P.D.,Debnath, A.K.
Structure-Based Design of a Small Molecule CD4-Antagonist with Broad Spectrum Anti-HIV-1 Activity.
J.Med.Chem., 58:6909-6927, 2015

PubMed Abstract: 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.

PubMed: 26301736
DOI: 10.1021/acs.jmedchem.5b00709

Experimental method

X-RAY DIFFRACTION (1.9 Å)