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 μM 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) ∼ 20 μM) is accompanied by the absence of toxicity in CEM T-cell line (CC(50) > 250 μM). 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.status: publishe

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 EC50 values in the lower μM 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 (EC50 ∼ 20 μM) is accompanied by the absence of toxicity in CEM T-cell line (CC50 > 250 μM). 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 KD: 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.V.L. thanks CSIC and the Fondo Social Europeo (FSE) for an I3P predoctoral contract.We thank María Nares and Leen Ingels for excellent technical assistance. Financial support to M. Nares by the Spanish MEC and the FSE is gratefully acknowledged. This work has been supported by a grant of the Spanish CICYT (SAF2009-13914-C02-01), the CSIC (PIF Programme ref LECTIVIR PIF08-022), the KU Leuven (GOA no. 10/014; EF 05/ 15; PF 10/018), the European Commission (CHAARM) and the FWO-Vlaanderen (no. G.485.08).Peer Reviewe