Zhang X, Gaubin M, Briant L, Srikantan V, Murali R, Saragovi U, Weiner D, Devaux C, Autiero M, Piatier-Tonneau D, Greene M I
Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-6082, USA.
Nat Biotechnol. 1997 Feb;15(2):150-4. doi: 10.1038/nbt0297-150.
CD4 functions as a major T-cell surface receptor for human immunodeficiency virus by binding the human immunodeficiency virus type 1 (HIV-1) envelope protein gp120 with relatively high affinity. We have developed constrained aromatically modified analogs of the secondary structures of the first domain of CD4 in order to analyze surfaces involved in binding of gp120. Complementarity determining-like regions (CDRs) of the D1 domain of CD4 were reproduced as synthetic aromatically modified exocyclic (AMEs) forms. The exocyclic CDR3.AME(82-89), derived from the CDR3 (residues 82-89) region of CD4 D1 domain, specifically inhibited binding of recombinant gp120 to both recombinant soluble CD4, and CD4+ Jurkat cells, and blocked syncytium formation and virus particle production caused by HIV-1 infection. We have previously shown that the CDR3.AME analog binds to the CD4 CDR3 region and creates a disabled CD4 heterodimer. We propose that the AME prevents the formation of an essential homodimeric surface needed for efficient HIV binding. Additionally the disabled CD4 receptor may be less able to signal the cell to allow HIV replication and HIV infection. Such compounds may represent a new receptor specific approach to modulate biological functions.
CD4作为人类免疫缺陷病毒的主要T细胞表面受体，通过以相对高的亲和力结合1型人类免疫缺陷病毒（HIV-1）包膜蛋白gp120发挥作用。我们开发了CD4第一结构域二级结构的受限芳香族修饰类似物，以分析参与gp120结合的表面。CD4 D1结构域的互补决定样区域（CDR）被复制为合成的芳香族修饰外环（AME）形式。源自CD4 D1结构域CDR3（第82-89位氨基酸残基）区域的外环CDR3.AME(82-89)，特异性抑制重组gp120与重组可溶性CD4以及CD4+ Jurkat细胞的结合，并阻断由HIV-1感染引起的合胞体形成和病毒颗粒产生。我们之前已表明，CDR3.AME类似物与CD4 CDR3区域结合并形成失活的CD4异二聚体。我们提出，AME可阻止形成高效HIV结合所需的必需同二聚体表面。此外，失活的CD4受体可能较难向细胞发出信号以允许HIV复制和HIV感染。此类化合物可能代表一种调节生物学功能的新型受体特异性方法。
