title: Structure-Based Design of a Small Molecule CD4-Antagonist with Broad Spectrum Anti-HIV-1 Activity.
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.
authors: Laboratory of Molecular Modeling and Drug Design, Lindsey F. Kimball Research Institute, New York Blood Center, New York, New York 10065, United States.
authors: Francesca
authors: F
authors: Curreli
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors: Young Do
authors: YD
authors: Kwon
authors: Laboratory of Molecular Modeling and Drug Design, Lindsey F. Kimball Research Institute, New York Blood Center, New York, New York 10065, United States.
authors: Hongtao
authors: H
authors: Zhang
authors: Laboratory of Molecular Modeling and Drug Design, Lindsey F. Kimball Research Institute, New York Blood Center, New York, New York 10065, United States.
authors: Daniel
authors: D
authors: Scacalossi
authors: EDASA Scientific, Scientific Park, Moscow State University, Leninskie Gory, Bld.75, 77-101b, 119992 Moscow, Russia.
authors: Dmitry S
authors: DS
authors: Belov
authors: EDASA Scientific, Scientific Park, Moscow State University, Leninskie Gory, Bld.75, 77-101b, 119992 Moscow, Russia.
authors: Artur A
authors: AA
authors: Tikhonov
authors: EDASA Scientific, Scientific Park, Moscow State University, Leninskie Gory, Bld.75, 77-101b, 119992 Moscow, Russia.
authors: Ivan A
authors: IA
authors: Andreev
authors: EDASA Scientific, Scientific Park, Moscow State University, Leninskie Gory, Bld.75, 77-101b, 119992 Moscow, Russia.
authors: Andrea
authors: A
authors: Altieri
authors: EDASA Scientific, Scientific Park, Moscow State University, Leninskie Gory, Bld.75, 77-101b, 119992 Moscow, Russia.
authors: Alexander V
authors: AV
authors: Kurkin
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors: Peter D
authors: PD
authors: Kwong
authors: Laboratory of Molecular Modeling and Drug Design, Lindsey F. Kimball Research Institute, New York Blood Center, New York, New York 10065, United States.
authors: Asim K
authors: AK
authors: Debnath
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015704:CD4 Antigens / Q000378:metabolism*; D002459:Cell Fusion; D002460:Cell Line; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism; D054303:HIV Reverse Transcriptase / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D010070:Oxalates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; C514246:N-(4-chlorophenyl)-N'-(2,2,6,6-tetramethylpiperidin-4-yl)oxalamide; C000603350:NBD-11021; D010070:Oxalates; D010880:Piperidines; D011758:Pyrroles; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D018894:Reverse Transcriptase Inhibitors; D013844:Thiazoles; D054303:HIV Reverse Transcriptase