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

Journal Article · · Journal of Medicinal Chemistry
 [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)
+ Show Author Affiliations

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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)
Grant/Contract Number:
W-31-109-Eng-38; RO1 AI104416
OSTI ID:
1222007
Journal Information:
Journal of Medicinal Chemistry, Vol. 58, Issue 17; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 45 works
Citation information provided by
Web of Science

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Cited By (12)

Novel one-pot expeditious synthesis of 2,4-disubstituted thiazoles through a three-component reaction under solvent free conditions text January 2018
In Silico Identification of Novel Aromatic Compounds as Potential HIV-1 Entry Inhibitors Mimicking Cellular Receptor CD4 journal August 2019
Computational design, synthesis and evaluation of new sulphonamide derivatives targeting HIV-1 gp120 journal December 2019
Antiviral Compounds from Myxobacteria journal July 2018
The first oxalamide-bridged ferrocene: Facile synthesis, preliminary conformational analysis and biological evaluation: The first oxalamide-bridged ferrocene journal November 2016
The Discovery and Development of Oxalamide and Pyrrole Small Molecule Inhibitors of gp120 and HIV Entry - A Review journal October 2019
Virtual screening and identification of potential HIV-1 inhibitors based on the cross-reactive neutralizing antibody N6 journal September 2019
Synthesis, Antiviral Activity, and Structure–Activity Relationship of 1,3‐Benzodioxolyl Pyrrole‐Based Entry Inhibitors Targeting the Phe43 Cavity in HIV‐1 gp120 journal October 2018
Novel one-pot expeditious synthesis of 2,4-disubstituted thiazoles through a three-component reaction under solvent free conditions journal December 2017
Small-molecule HIV-1 entry inhibitors targeting gp120 and gp41: a patent review (2010-2015) journal January 2017
Novel one-pot expeditious synthesis of 2,4-disubstituted thiazoles through a three-component reaction under solvent free conditions text January 2018
Virtual Screening, Biological Evaluation, and 3D-QSAR Studies of New HIV-1 Entry Inhibitors That Function via the CD4 Primary Receptor journal November 2018

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