Short Communication: Pharmacophore Determination of a gp120 C Terminal-Derived Anti-HIV Peptide Construct Interfering with Membrane Fusion Suggesting That Processing of the gp120 C Terminus Is a Prelude to Fusion

A multiple antigen peptide [CLIV; (PTKAKRR₁VVQREKR₂)₄-K₂-K-βA] from the C terminus of the gp120 subunit of HIV Env inhibits Env-mediated cell-to-cell fusion through direct interference with the process (Virology 2000;273:169). We have examined various CLIV analogs using a cell-to-cell fusion assay, receptor binding assays, and molecular modeling to further address the characteristics of the peptide responsible for its anti-HIV activity. We show that (1) CLIV does not interfere with Env binding to CD4 and does not interact with the binding site of Env on CXCR4;(2) CLIV does not inhibit protease activities already reported to play a role in fusion; and (3) the pharmacophore is composed of cleavage site₁ with amino acid residues at its C terminal end. Based on our data and on the literature, we propose that CLIV interferes with processing of the gp120 C terminus at site₁ by the lymphocyte surface after CD4 binding. Our hypothesis implies that the cleavage region of Env is submitted to a stepwise processing including the known intracellular cleavage of gp160 at site₂ in order to set the activation of the fusion peptide and a yet unexplored cleavage at site₁ by the target cell surface that triggers fusion.