Highly Potent Synthetic Polyamides, Bisdistamycins, and Lexitropsins as Inhibitors of Human Immunodeficiency Virus Type 1 Integrase

Abstract

Alignment of the available human immunodeficiency virus type 1 (HIV-1) viral DNA termini [U5 and U3 long terminal repeats (LTRs)] shows a high degree of conservation and the presence of a stretch of five or six consecutive adenine and thymine (AT) sequences approximately 10 nucleotides away from each LTR end. A series of AT-selective minor-groove binders, including distamycin and bisdistamycins, bisnetropsins, novel lexitropsins, and the classic monomeric DNA binders Hoechst 33258, 4'-diamino-2-phenylindole, pentamidine, berenil, spermine, and spermidine, were 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 microM, some of the polyamides, bisdistamycins, and lexitropsins were remarkably active at nanomolar concentrations. Bisdistamycins were 200 times less potent when the conserved AAAAT stretch present in the U5 LTR was replaced with GGGGG, consistent with the preferred binding of these drugs to AT sequences. DNase I footprinting of the U5 LTR further demonstrated the selectivity of these bisdistamycins for the conserved AT sequence. The tested compounds were more potent in Mg+2 than in Mn+2 and inhibited IN50-212 deletion mutant in disintegration assays and the formation of IN/DNA 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 might represent new leads for the development of antiviral agents against acquired immune deficiency syndrome.

Position-specific Suppression and Enhancement of HIV-1 Integrase Reactions by Minor Groove Benzo[a]pyrene Diol Epoxide Deoxyguanine Adducts

“…Synthetic polyamines such as the lexitropsins selectively bind the minor groove of the conserved AAAAT stretch of the HIV-1 LTRs and inhibit integrase at nanomolar concentrations (30). The results presented here suggest that targeting the minor groove of the HIV-1 DNA near the integrase 3Ј-P site may also effectively inhibit integrase activity.…”

DNA minor groove binders as potential antitumor and antimicrobial agents

“…These compounds demonstrated significant antiretroviral activity, especially as inhibitors of Human immunodeficiency virus (HIV), if compared to the distamycin A. 172,173 All the synthesized compounds were tested for their inhibition activity on HIV-1 replication in CEM cell line, and in this series of derivatives, the compound 115, which possesses the terephthaloyl moiety as linker, was approximately eightfold more potent than the distamycin A.…”

New anti‐HIV agents and targets

“…Since HIV, like other retroviruses, cannot replicate without integration into a host chromosome, integrase has been considered as an attractive therapeutic target. Numerous compounds have been described as inhibitors of HIV-1 integrase (for a recent review, see Pommier et al 135 ): for example, polyamides, bisdistamycins and lexitropsins, 136 polyhydroxylated aromatic type of compounds, including ellagic acid, purpurogallin, 4,8,12-trioxatricornan and hypericin, 137 and a series of thiazolothiazepine derivatives, preferably possessing the pentatomic moiety SC(O)CNC(O) with two carbonyl groups. 138 The problem with integrase inhibitors is that while they might be effective in an enzyme-based assay, their anti-HIV activity in cell culture may be masked by cytotoxicity, and if they do exhibit anti-HIV activity, this could, at least in some cases, be attributed to antiviral actions targeted at other steps in the HIV replicative cycle.…”