4rz8

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

Structural highlights

4rz8 is a 4 chain structure with sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.9Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

A0A0M3KKW9_9HIV1

Publication Abstract from PubMed

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.

Structure-Based Design of a Small Molecule CD4-Antagonist with Broad Spectrum Anti-HIV-1 Activity.,Curreli F, Kwon YD, Zhang H, Scacalossi D, Belov DS, Tikhonov AA, Andreev IA, Altieri A, Kurkin AV, Kwong PD, Debnath AK J Med Chem. 2015 Aug 28. PMID:26301736[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. Curreli F, Kwon YD, Zhang H, Scacalossi D, Belov DS, Tikhonov AA, Andreev IA, Altieri A, Kurkin AV, Kwong PD, Debnath AK. Structure-Based Design of a Small Molecule CD4-Antagonist with Broad Spectrum Anti-HIV-1 Activity. J Med Chem. 2015 Aug 28. PMID:26301736 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00709

4rz8, resolution 1.90Å

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OCA