Targeting HIV Entry through Interaction with Envelope Glycoprotein 120 (gp120): Synthesis and Antiviral Evaluation of 1,3,5-Triazines with Aromatic Amino Acids

On the basis of the interesting inhibitory properties that lectins show against HIV-replication through their interaction with glycoprotein 120 (gp120), we here describe the design, synthesis, and anti-HIV evaluation of three series of 1,3,5-triazine derivatives (monomers, dimers, and trimers) functionalized with aromatic amino acids meant to mimic interactions that lectins establish with gp120. While monomers were inactive against HIV replication, dimers showed limited anti-HIV activity that is, however, considerably more significant in the trimers series, with EC(50) values in the lower mu M range. These findings most likely reflect the requirement of multivalency of the 1,3,5-triazine derivatives to display anti-HIV activity, as lectins do. The pronounced anti-HIV activity (EC(50) similar to 20 mu M) is accompanied by the absence of toxicity in CEM T-cell line (CC(50) > 250 mu M). Moreover, SPR experiments revealed that the prototype trimers with a central core of 2,4,6-triethylbenzene and six L-Trp or six L-Tyr residues at the periphery were efficient binders of CXCR4- and CCR5-tropic HIV-1 gp120 (estimated K(D): lower micromolar range). The collected data support the interest of this novel family of anti-HIV agents and qualify them as potential novel microbicide lead compounds.