HIGHLY POTENT SYNTHETIC POLYAMIDES, BISDISTAMYCINS, AND LEXITROPSINS AS INHIBITORS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 INTEGRASE

Alignment of the available human immunodeficiency virus type 1 (HIV-1) viral DNA termini [U5 and U3 long terminal repeats (LTRs)] shows a hi gh degree of conservation and the presence of a stretch of five or six consecutive adenine and thymine (AT) sequences similar to 10 nucleoti des away from each LTR end. A series of AT-selective minor-groove bind ers, including distamycin and bisdistamycins, bisnetropsins, novel lex itropsins, and the classic monomeric DNA binders Hoechst 33258, 4'-dia mino-2-phenylindole, pentamidine, berenil, spermine, and spermidine, w ere tested for their inhibitory activities against HIV-1 integrase (IN ). Although netropsin, distamycin, and all other monomeric DNA binders showed weak activities in the range of 50-200 mu M, some of the polya mides, bisdistamycins, and lexitropsins were remarkably active at nano molar concentrations. Bisdistamycins were 200 times less potent when t he conserved AAAAT stretch present in the U5 LTR was replaced with GGG GG, consistent with the preferred binding of these drugs to AT sequenc es. DNase I footprinting of the U5 LTR further demonstrated the select ivity of these bisdistamycins for the conserved AT sequence. The teste d compounds were more potent in Mg+2 than in Mn+2 and inhibited IN50-2 12 deletion mutant in disintegration assays and the formation of IN/DN A complexes. The lexitropsins also were active against HIV-2 IN. Some of the synthetic polyamides exhibited significant antiviral activity. Taken together, these data suggest that selective targeting of the U5 and U3 ends of the HIV-1 LTRs can inhibit IN function. Polyamides migh t represent new leads for the development of antiviral agents against acquired immune deficiency syndrome.