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.