Didier Esquieu, Jean-Marie Péloponèse, Sandrine Opi, Catherine Gregoire, Jean de Mareuil, Jennifer Watkins, Grant Campbell, Jean-Pierre Dunot, James Sturgis, Myriam Witvrouw, Christophe Pannecouque, Erik de Clercq, Mickaël Montembault, Vo-Thanh Giang, Monique Villiéras, Valérie Fargeas, Jacques Lebreton, Erwann P. Loret, "Discovery of a Tat HIV-1 Inhibitor through Computer-Aided Drug Design", Journal of Spectroscopy, vol. 17, Article ID 283731, 7 pages, 2003. https://doi.org/10.1155/2003/283731
Discovery of a Tat HIV-1 Inhibitor through Computer-Aided Drug Design
Tat is a regulatory HIV-1 protein, which has the particularity to be secreted very early by HIV-infected cells. The extra cellular roles of Tat are suspected to be the main cause of the maintenance of reservoirs of HIV-infected cells and the failure of actual AIDS therapies to eradicate HIV. This study describes the rationale used to design molecules that bind to a target area containing an hydrophobic pocket identified in the 2D-NMR structure of Tat. Molecules were synthesized and the derivative named TDS2 was shown to be a Tat inhibitor. Fluorescence revealed that TDS2 binds in the target area, which is conserved across five different Tat variants representative of the main HIV-1 subtypes. TDS2 inhibited in vitro HIV-1 replication in human T-cells. Further chemical modifications remain necessary to enhance affinity to Tat and reduce cytotoxicity.
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