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

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• 作者：Virginia Lozano ; Leire Aguado ; Bart Hoorelbeke ; Marleen Renders ; Mar铆a-Jos茅 Camarasa ; Dominique Schols ; Jan Balzarini ; Ana San-F茅lix ; Mar铆a-Jes煤s P茅rez-P茅rez
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：August 11, 2011
• 年：2011
• 卷：54
• 期：15
• 页码：5335-5348
• 全文大小：1152K
• 年卷期：v.54,no.15(August 11, 2011)
• ISSN：1520-4804

文摘

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 渭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 (EC₅₀ 20 渭M) is accompanied by the absence of toxicity in CEM T-cell line (CC₅₀ > 250 渭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.