Anti-Tat and anti-HIV activities of trimers of n-alkylglycines

9 pages, 7 figures.Transcription of human immunodeficiency virus (HIV-1) is activated by viral Tat protein which regulates HIV–LTR transcription and elongation. In the present report, the evaluation of the anti-Tat activity of a combinatorial library composed of 5120 N-trialkylglycines is reported. The antiviral activity was studied through luciferase-based assays targeting the HIV-1 promoter activation induced by the HIV-1 Tat protein. We identified five peptoids with specific anti-HIV-1 Tat activity; none of these peptoids affected the binding of HIV-1 Tat protein to the viral TAR RNA. Using a recombinant-virus assay in which luciferase activity correlates with the rate of HIV-1 transcription we have detected that one of the five selected peptoids, NC37-37-15C, is a potent inhibitor of HIV-1–LTR transcription in both primary T lymphocytes and transformed cell lines. The inhibitory effect of NC37-37-15C, which is additive with azidothymidine (AZT), correlates with its ability to inhibit CTD phosphorylation and shows a suitable profile for development of novel anti-HIV-1 drugs. Likewise, the structural simplicity of N-alkylglycine oligomers makes these peptidomimetics amenable to structural manipulation, thus facilitating the optimisation of lead molecules for drug-like properties.This work was supported by Ministerio de Educación y Ciencia Grant SAF2004-00926 and Fondo de Investigación Sanitaria PI040526 to EM, and Ministerio de Ciencia y Tecnología SAF2001-2286 and Fundació Marató TV3 (2004) to AM.Peer reviewe