Structure-Based Design and Synthesis of an HIV-1 Entry Inhibitor Exploiting X-ray and Thermodynamic Characterization

详细信息    查看全文

• 作者：Judith M. LaLonde ; Matthew Le-Khac ; David M. Jones ; Joel R. Courter ; Jongwoo Park ; Arne Sch枚n ; Amy M. Princiotto ; Xueling Wu ; John R. Mascola ; Ernesto Freire ; Joseph Sodroski ; Navid Madani ; Wayne A. Hendrickson ; Amos B. Smith ; III
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：March 14, 2013
• 年：2013
• 卷：4
• 期：3
• 页码：338-343
• 全文大小：377K
• 年卷期：v.4,no.3(March 14, 2013)
• ISSN：1948-5875

文摘

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 渭M, 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鈥揼p120 interface is an effective tactic to enhance the neutralization potency of small-molecule HIV-1 entry inhibitors.

Keywords:

HIV; gp120; CD4; entry inhibitor; structure-based drug design; thermodynamics; X-ray crystallography; viral inhibition; protein鈭抪rotein interactions