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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-HIV Agents / chemical synthesis
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Anti-HIV Agents / chemistry*
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Anti-HIV Agents / pharmacology
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CD4 Antigens / metabolism*
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Cell Fusion
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Cell Line
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HIV Envelope Protein gp120 / chemistry
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HIV Envelope Protein gp120 / metabolism
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HIV Reverse Transcriptase / metabolism
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HIV-1 / drug effects*
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HIV-1 / isolation & purification
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HIV-1 / physiology
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Humans
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Hydrogen Bonding
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Models, Molecular
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Molecular Conformation
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Oxalates / chemical synthesis
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Oxalates / chemistry*
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Oxalates / pharmacology
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Piperidines / chemical synthesis
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Piperidines / chemistry*
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Piperidines / pharmacology
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Protein Conformation
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Pyrroles / chemical synthesis
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Pyrroles / chemistry*
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Pyrroles / pharmacology
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Receptors, CCR5 / metabolism
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Receptors, CXCR4 / metabolism
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Reverse Transcriptase Inhibitors / chemical synthesis
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Reverse Transcriptase Inhibitors / chemistry
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Reverse Transcriptase Inhibitors / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Thiazoles / chemical synthesis
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Thiazoles / chemistry*
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Thiazoles / pharmacology
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Virus Internalization / drug effects
Substances
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Anti-HIV Agents
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CD4 Antigens
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HIV Envelope Protein gp120
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N-(4-chlorophenyl)-N'-(2,2,6,6-tetramethylpiperidin-4-yl)oxalamide
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NBD-11021
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Oxalates
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Piperidines
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Pyrroles
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Receptors, CCR5
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Receptors, CXCR4
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Reverse Transcriptase Inhibitors
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Thiazoles
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HIV Reverse Transcriptase