Mechanism of action and structure-activity studies of norspermidine based peptidic inhibitors of trypanothione reductase

Abstract

Infection by Trypanosoma and Leishmania parasites cause several diseases of major importance to third world health.  These particles are highly susceptible to oxidative stress, but help to maintain their intra-cellular redox balance by utilising the enzyme trypanothione reductase (TR) and the metabolite trypanothione disulfide, rather than the analogous glutathione reductase (GR) and glutathione found in mammalian cells.  Despite sharing many similarities, TR and GR exhibit a high degree of selectivity for their respective substrates and thus TR has emerged as a highly promising target for the development of anti-parasitic drugs.

This thesis describes an investigation into the mechanism of action of a previously identified class of trypanothione reductase inhibitors by a variety of techniques including kinetic analysis, analytical ultracentrifugation, gel filtration chromatography and protein crystallography, leading to the identification of an allosteric mode of inhibition.

A library of simplified structural analogues of the lead compounds were screened and active compounds subjected to full kinetic analysis, to establish structure activity relationships (SAR) where subtle structural changes were found to cause changes in inhibition mechanism.

These findings give a better understanding of the enzymes of mode of action and this class of inhibitors and will aid the development of more effective enzyme inhibitors in the future.

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