title: Structure-Based Design and Synthesis of an HIV-1 Entry Inhibitor Exploiting X-Ray and Thermodynamic Characterization.
abstract: The design, synthesis, thermodynamic and crystallographic characterization of a potent, broad spectrum, second-generation HIV-1 entry inhibitor that engages conserved carbonyl hydrogen bonds within gp120 has been achieved. The optimized antagonist exhibits a sub-micromolar binding affinity (110 nM) and inhibits viral entry of clade B and C viruses (IC50geometric mean titer of 1.7 and 14.0 μM, respectively), without promoting CD4-independent viral entry. thermodynamic signatures indicate a binding preference for the (R,R)-over the (S,S)-enantiomer. The crystal structure of the small molecule-gp120 complex reveals the displacement of crystallographic water and the formation of a hydrogen bond with a backbone carbonyl of the bridging sheet. Thus, structure-based design and synthesis targeting the highly conserved and structurally characterized CD4:gp120 interface is an effective tactic to enhance the neutralization potency of small molecule HIV-1 entry inhibitors.
authors.affiliation: Department of Chemistry, Bryn Mawr College, Bryn Mawr, PA 19010.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Lalonde
authors.forename: Matthew
authors.initials: M
authors.lastname: Le-Khac
authors.forename: David M
authors.initials: DM
authors.lastname: Jones
authors.forename: Joel R
authors.initials: JR
authors.lastname: Courter
authors.forename: Jongwoo
authors.initials: J
authors.lastname: Park
authors.forename: Arne
authors.initials: A
authors.lastname: Schön
authors.forename: Amy M
authors.initials: AM
authors.lastname: Princiotto
authors.forename: Xueling
authors.initials: X
authors.lastname: Wu
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.forename: Ernesto
authors.initials: E
authors.lastname: Freire
authors.forename: Joseph
authors.initials: J
authors.lastname: Sodroski
authors.forename: Navid
authors.initials: N
authors.lastname: Madani
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Hendrickson
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
keywords: CD4; HIV; entry inhibitor; gp120; protein-protein interactions; structure-based drug design; thermodynamics; viral inhibition; x-ray crystallography