Combinatorial chemistry and polyamines in the battle against Typanosomes and Leishmanias

Smith, Helen Katherine (1998) Combinatorial chemistry and polyamines in the battle against Typanosomes and Leishmanias. University of Southampton, Doctoral Thesis.

Abstract

The Trypanosoma and Leishmania parasites are responsible for the infection of several million people and animals worldwide, causing widespread disease and fatalities. These parasites are highly susceptible to oxidative stress, yet maintenance of a reducing cellular environment is not carried out in these organisms by the usually ubiquitous glutathione/glutathione reductase (GR) system. This rôle is assumed by the unique metabolite trypanothione (N¹, N⁸, -bis(glutathionyl)spermidine) and its enzyme trypanothione reductase (TR). The high substrate specificity of both these enzymes makes TR a potential target for antitrypanosomal drug design.

This thesis describes the development of novel polyamine templates for attachment to the solid phase based on the spermidine backbone of trypanothione. The solid phase synthesis of trypanothione has been followed by the preparation of several thousand polyamine-peptide conjugates for screening against trypanothione reductase, via the technique of combinatorial chemistry. These libraries of compounds have been screened using several different methodologies, either in solution or whilst tethered to the solid support. Several potent inhibitors of TR have been discovered and resynthesised from screening a 576-member solution library. K_i values have been determined with values as low as 100 nM.

The same library has been prepared and secreened using three different techniques giving a direct comparison of each method. The results corresponded completely, from similar structural characteristics to identical compounds. Strong binding motifs have become apparent which are in accordance with the majority of TR inhibitors reported to date. Polyamines displaying high affinities to TR are conjugated to a positively charged moiety (at physiological pH i.e. arginine) followed by a small aromatic or hydrophobic group (i.e. tryptophan, tyrosine or phenylalanine).

The success of these screens gives a wider scope for the discovery of even more potent inhibitors of TR and potentially novel chemotherapeutic agents against trypanosomal disease.

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