title: Structure-based design, synthesis, and characterization of dual hotspot small-molecule HIV-1 entry inhibitors.
abstract: Cellular infection by HIV-1 is initiated with a binding event between the viral envelope glycoprotein gp120 and the cellular receptor protein CD4. The CD4-gp120 interface is dominated by two hotspots: a hydrophobic gp120 cavity capped by Phe43(CD4) and an electrostatic interaction between residues Arg59(CD4) and Asp368(gp120). The CD4 mimetic small-molecule NBD-556 (1) binds within the gp120 cavity; however, 1 and related congeners demonstrate limited viral neutralization breadth. Herein, we report the design, synthesis, characterization, and X-ray structures of gp120 in complex with small molecules that simultaneously engage both binding hotspots. The compounds specifically inhibit viral infection of 42 tier 2 clades B and C viruses and are shown to be antagonists of entry into CD4-negative cells. Dual hotspot design thus provides both a means to enhance neutralization potency of HIV-1 entry inhibitors and a novel structural paradigm for inhibiting the CD4-gp120 protein-protein interaction.
authors.affiliation: Department of Chemistry, Bryn Mawr College, Bryn Mawr, Pennsylvania 19010, USA. jlalonde@brynmawr.edu
authors.forename: Judith M
authors.initials: JM
authors.lastname: LaLonde
authors.forename: Young Do
authors.initials: YD
authors.lastname: Kwon
authors.forename: David M
authors.initials: DM
authors.lastname: Jones
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Sun
authors.forename: Joel R
authors.initials: JR
authors.lastname: Courter
authors.forename: Takahiro
authors.initials: T
authors.lastname: Soeta
authors.forename: Toyoharu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Amy M
authors.initials: AM
authors.lastname: Princiotto
authors.forename: Xueling
authors.initials: X
authors.lastname: Wu
authors.forename: Arne
authors.initials: A
authors.lastname: Schön
authors.forename: Ernesto
authors.initials: E
authors.lastname: Freire
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.forename: Joseph
authors.initials: J
authors.lastname: Sodroski
authors.forename: Navid
authors.initials: N
authors.lastname: Madani
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
mesh_terms: D015704:CD4 Antigens / Q000378:metabolism; D002151:Calorimetry / Q000379:methods; D018360:Crystallography, X-Ray; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007189:Indans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009500:Neutralization Tests / Q000379:methods; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D007189:Indans