Structure-Activity Relationships in the Binding of Chemically Derivatized CD4 to gp120 from Human Immunodeficiency Virus

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• 作者：Hui Xie ; Danny Ng ; Sergey N. Savinov ; Barna Dey ; Peter D. Kwong ; Richard Wyatt ; Amos B. Smith ; III ; Wayne A. Hendrickson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：October 4, 2007
• 年：2007
• 卷：50
• 期：20
• 页码：4898 - 4908
• 全文大小：331K
• 年卷期：v.50,no.20(October 4, 2007)
• ISSN：1520-4804

文摘

The first step in HIV infection is the binding of the envelope glycoprotein gp120 to the host cell receptorCD4. An interfacial "Phe43 cavity" in gp120, adjacent to residue Phe43 of gp120-bound CD4, has beensuggested as a potential target for therapeutic intervention. We designed a CD4 mutant (D1D2F43C) forsite-specific coupling of compounds for screening against the cavity. Altogether, 81 cysteine-reactivecompounds were designed, synthesized, and tested. Eight derivatives exceeded the affinity of native D1D2for gp120. Structure-activity relationships (SAR) for derivatized CD4 binding to gp120 revealed significantplasticity of the Phe43 cavity and a narrow entrance. The primary contacts for compound recognition insidethe cavity were found to be van der Waals interactions, whereas hydrophilic interactions were detected inthe entrance. This first SAR on ligand binding to an interior cavity of gp120 may provide a starting pointfor structure-based assembly of small molecules targeting gp120-CD4 interaction.