Inhibition of Human Immunodeficiency Virus Type I Reverse Transcriptase by Suramin-related Compounds

Abstract

SUMMARYNinety analogues of suramin have been examined for their ability to inhibit the exogenous reverse transcriptase (RT) of human immunodeficiency virus type I (HIV-I). Of these compounds, 57 inhibited the poly(rC)-oligo(dG)-dependent RT activity. Three classes of dose-response curves could be discriminated. Allocation of a compound to one class did not correspond with obvious structural features. Twentyfour substances were superior to suramin in our RT inhibition assay. The RTinhibitory activity of these compounds did not correlate with their effect against filariae or trypanosomes. Preliminary antiviral evaluation in susceptible human T cells inoculated with HIV-I demonstrated in vitro therapeutic efficacy for some compounds with lower drug-related cellular toxicity than suramin. Certain structural features relevant for the RT-inhibitory effect of these compounds were recognized. Predictions are made for the design of more effective RT inhibitors. Such compounds will help to understand the molecular mechanism of reverse transcription and might be useful in the therapy of retroviral infections.

A structure-activity analysis of antagonism of the growth factor and angiogenic activity of basic fibroblast growth factor by suramin and related polyanions

“…For example, CPD16 (see Figure 2, below), in which the two methyl groups of suramin are replaced by hydrogen, has only about 5% of the trypanocidal activity of suramin (Fourneau et al, 1924). In contrast, inhibition of HIV-1 reverse transcriptase is much less sensitive to structural modification and the structure-activity relationships are completely different from those of its trypanocidal or antifilarial activity (Jentsch et al, 1987).…”

A trypanosome oligopeptidase as a target for the trypanocidal agents pentamidine, diminazene and suramin

“…Replacing each of the l-naphthylamino-4,6,8-trisulfonic acid moieties of suramin with aniline-2,4-disulfonic acid (NF065: Analogue nomenclature is detailed in [19].…”

“…Subsequent removal of two of these 4-C-benzoyl groups n.m. denotes that no inhibitory activity was observed at the concentrations tested. Analogue nomenclature is detailed in [19].…”

“…Analogues were synthesized as described previously [18] with various substitutions at RL, R~ and R:~ (Tables 1 and 2). Analogue nomenclature is adapted from that described in [19]. [9] and active enzyme concentration determined using 4-methylumbelliferyl-p-guanidobenzoate as described [20].…”

Kinetics of inhibition of sperm β‐acrosin activity by suramin

“…1) that was originally synthesised as a trypanocidal agent for treatment of sleeping sickness in East Africa [12]. Lately, it has found diverse applications as an anticancer drug because of its ability to block angiogenesis, inhibit reverse transcriptase and cause microaggregation of growth factors [13,14]. Although suramin binds to a variety of proteins (e.g.…”