RATIONAL DESIGN OF PEPTIDE-BASED INHIBITORS OF TRYPANOTHIONE REDUCTASE AS POTENTIAL ANTITRYPANOSOMAL DRUGS

The rational design of ligands for the substrate-binding site of a homology-modelled trypanothione reductase (TR) was performed. Peptides were designed to be selective for TR over human glutathione reductase (GR). The design process capitalized on the proposed differences between the active-sites of TR and human GR, subsequently confirmed by the TR crystal structure. Enzyme kinetics confirmed that for T. cruzi TR benzoyl-Leu-Arg-Arg-beta-naphthylamide was an inhibitor (K-i 13.8 mu M) linearly competitive with the native substrate, trypanothione disulphide, and did not inhibit glutathione reductase.