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 hom ology-modelled trypanothione reductase (TR) was performed. Peptides we re designed to be selective for TR over human glutathione reductase (G R). 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 ben zoyl-Leu-Arg-Arg-beta-naphthylamide was an inhibitor (K-i 13.8 mu M) l inearly competitive with the native substrate, trypanothione disulphid e, and did not inhibit glutathione reductase.