Certification of the Critical Importance of l-3-(2-Naphthyl)alanine at Position 3 of a Specific CXCR4 Inhibitor, T140, Leads to an Exploratory Performance of Its Downsizing Study Original Research Article

We have previously found that a 14-amino acid residue-peptide, T140, inhibits infection of target cells by T cell line-tropic HIV-1 (X4-HIV-1) through its specific binding to a chemokine receptor, CXCR4. Here, the importance of an l-3-(2-naphthyl)alanine (Nal) residue at position 3 in T140 for high anti-HIV activity and inhibitory activity against Ca2+ mobilization induced by stromal cell-derived factor (SDF)-1α-stimulation through CXCR4 has initially been shown by the synthesis and biological evaluation of several analogues, where Nal3 is substituted by diverse aromatic amino acids. Next, the order of the N-terminal 3 residues (Arg1-Arg2-Nal3) has been proved to be important from the structure–activity relationship (SAR) study shuffling these residues. Based on these results, we have found 10-residue peptides possessing modest anti-HIV activity by systematic antiviral evaluation of a series of synthetic, shortened analogues of T140.