Inhibition of HIV-1 integrase-catalysed reaction by new DNA minor groove ligands: the oligo-1,3-thiazolecarboxamide derivatives

Human immunodeficiency virus type 1 (HIV-1) integrase (IN) is an essential enzyme in the life cycle of the retrovirus, responsible for catalysing the insertion of the viral genome into the host cell chromosome. For this reaso n it provides an attractive target for antiviral drug design. We synthesize d a series of novel thiazole (Tz)-containing oligopeptides (TCOs; oligo-1,3 -thiazolecarboxamides), specifically interacting within the minor groove of DNA. The oligocarboxamide derivatives contained 1-4 Tz rings and different N- and C-terminal groups. The effect of these oligocarboxamides on the HIV -1 IN-catalysed reaction was investigated. Some of the compounds were able to inhibit the reaction. The inhibitory effect of the TCOs increased with t he number of Tz units. The structure of various additional positively and/o r negatively charged groups attached to the N- and C-termini of TCOs had a pronounced effect on their interaction with the DNA substrate complexed to IN. Modified TCOs having a better affinity for this complex should provide a rationale for the design of drugs targeting the integration step. (C) 200 0 Editions scientifiques et medicales Elsevier SAS.