Specific peptide inhibitors of trypanothione reductase with backbone structures unrelated to that of substrate: potential rational drug design lead frameworks

By introducing cationic charge sites novel peptide lead inhibitor structure s for trypanothione reductase have been designed using molecular modelling methods. The inhibitors showed reversible, linear competitive inhibition an d the strongest peptide inhibitor to date was found to be N-benzyloxycarbon yl-Ala-Arg-Arg-4-methoxy-beta -naphthylamide with a K-i value of 2.4 muM an d a selectivity for parasitic enzyme (trypanothione reductase) over the hos t enzyme (human glutathione reductase) of over 3 orders of magnitude.