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Title: 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 in this paper, 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.
Authors:
 [1] ;  [2] ;  [1] ;  [1] ;  [3] ;  [3] ;  [3] ;  [3] ;  [3] ;  [2] ;  [1]
  1. New York Blood Center, New York, NY (United States). Lindsey F. Kimball Research Inst., Lab. of Molecular Modeling and Drug Design
  2. National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Allergy and Infectious Diseases, Vaccine Research Center
  3. Moscow State Univ., Moscow (Russian Federation)
Publication Date:
OSTI Identifier:
1222007
Grant/Contract Number:
W-31-109-Eng-38; RO1 AI104416
Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 58; Journal Issue: 17; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES