Peptoid inhibition of trypanothione reductase as a potential antitrypanosomal and antileishmanial drug lead

TY - JOUR

T1 - Peptoid inhibition of trypanothione reductase as a potential antitrypanosomal and antileishmanial drug lead

AU - Chan, C.

AU - Yin, H.

AU - McKie, J. H.

AU - Fairlamb, A. H.

AU - Douglas, K. T.

PY - 2002/6

Y1 - 2002/6

N2 - One route to the design of lead compounds for rational drug design approaches to developing drugs against trypanosomiasis, Chagas' disease and leishmaniasis is to develop novel inhibitors of the parasite-specific enzyme trypanothione reductase. A lead inhibitor based on a peptoid structure was designed in the present study based on the known strong competitive inhibition of trypanothione reductase by N-benzoyl-Leu-Arg-Arg-β-naphthylamide and N-benzyloxycarbonyl-Ala-Arg-Arg-4-methoxy-β-naphthylamide. In the target peptoid the arginyl residues were replaced by alkylimidazolium units and the benzyloxycarbonyl group by the benzylaminocarbonyl function. The peptoid was synthesised using t-butoxycarbonyl protection chemistry and couplings were activated by 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate. The resulting peptoid was shown to be a competitive inhibitor of recombinant trypanothione reductase from Trypanosoma cruzi with a Ki value of 179μM and with only weak inhibition of human erythrocyte glutathione reductase (the inhibition of glutathione reductase was at least 291-fold weaker than of trypanothione reductase).

AB - One route to the design of lead compounds for rational drug design approaches to developing drugs against trypanosomiasis, Chagas' disease and leishmaniasis is to develop novel inhibitors of the parasite-specific enzyme trypanothione reductase. A lead inhibitor based on a peptoid structure was designed in the present study based on the known strong competitive inhibition of trypanothione reductase by N-benzoyl-Leu-Arg-Arg-β-naphthylamide and N-benzyloxycarbonyl-Ala-Arg-Arg-4-methoxy-β-naphthylamide. In the target peptoid the arginyl residues were replaced by alkylimidazolium units and the benzyloxycarbonyl group by the benzylaminocarbonyl function. The peptoid was synthesised using t-butoxycarbonyl protection chemistry and couplings were activated by 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate. The resulting peptoid was shown to be a competitive inhibitor of recombinant trypanothione reductase from Trypanosoma cruzi with a Ki value of 179μM and with only weak inhibition of human erythrocyte glutathione reductase (the inhibition of glutathione reductase was at least 291-fold weaker than of trypanothione reductase).

KW - Antiparasitics

KW - Drug leads

KW - Enzyme inhibitors

KW - Glutathione

KW - Rational drug design

UR - https://www.scopus.com/pages/publications/0036281756

U2 - 10.1007/s007260200016

DO - 10.1007/s007260200016

M3 - Article

C2 - 12107758

AN - SCOPUS:0036281756

SN - 0939-4451

VL - 22

SP - 297

EP - 308

JO - Amino Acids

JF - Amino Acids

IS - 4

ER -