- CD4-MIMETIC INHIBITORS OF HIV-1 ENTRY AND METHODS OF USE THEREOF
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Described herein are small-molecule mimics of CD4, which both enter the Phe43 cavity and target Asp368 of gpl20, the HIV-1 envelope protein. Also described herein are methods of using these compounds to inhibit the transmission or progression of HIV infection. These compounds exhibit antiviral potency greater than that of a known antiviral, NBD-556, with 100% breadth against clade B and C viruses. Importantly, the compounds do not activate HIV infection of CD4-negative, CCR5-positive cells, in contrast to NBD- 556.
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- Structure-based design and synthesis of an HIV-1 entry inhibitor exploiting X-ray and thermodynamic characterization
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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 submicromolar binding affinity (110 nM) and inhibits viral entry of clade B and C viruses (IC50 geometric mean titer of 1.7 and 14.0 μM, respectively), without promoting CD4-independent viral entry. The 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.
- LaLonde, Judith M.,Le-Khac, Matthew,Jones, David M.,Courter, Joel R.,Park, Jongwoo,Schoen, Arne,Princiotto, Amy M.,Wu, Xueling,Mascola, John R.,Freire, Ernesto,Sodroski, Joseph,Madani, Navid,Hendrickson, Wayne A.,Smith, Amos B.
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supporting information
p. 338 - 343
(2013/05/08)
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