Discovery of a Tat HIV‐1 inhibitor through computer‐aided drug design

Article type: Research Article

Authors: Esquieu, Didier | Péloponèse, Jean‐Marie | Opi, Sandrine | Gregoire, Catherine | de Mareuil, Jean | Watkins, Jennifer | Campbell, Grant | Dunot, Jean‐Pierre | Sturgis, James | Witvrouw, Myriam | Pannecouque, Christophe | de Clercq, Erik | Montembault, Mickaël | Giang, Vo‐Thanh | Villiéras, Monique | Fargeas, Valérie | Lebreton, Jacques | Loret, Erwann P.^;

Affiliations: CNRS UMR 6032, Faculté de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille, France | CNRS UPR 9027, Institut de Biologie Structurale et Microbiologie, 31 Chemin Joseph Aiguier, 13402 Marseille, France | Rega Institute for Medical Research, K.U. Leuven Minderbroedersstraat 10, B‐3000 Leuven, Belgium | CNRS UMR 6512, Faculté des Sciences et des Techniques, 2 rue de la Houssinière, 44222 Nantes, France

Note: [] Corresponding author. E‐mail: [email protected]‐mrs.fr.

Abstract: 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.

Journal: Spectroscopy, vol. 17, no. 4, pp. 639-645, 2003