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Targeting a Large Active Site: Structure‐Based Design of Nanomolar Inhibitors of Trypanosoma brucei Trypanothione Reductase
Author(s) -
De Gasparo Raoul,
Halgas Ondrej,
Harangozo Dora,
Kaiser Marcel,
Pai Emil F.,
KrauthSiegel R. Luise,
Diederich François
Publication year - 2019
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201901664
Subject(s) - trypanosoma brucei , active site , ic50 , biochemistry , hepes , binding site , enzyme , chemistry , in vivo , in vitro , glutathione , biology , stereochemistry , microbiology and biotechnology , gene
Trypanothione reductase (TR) plays a key role in the unique redox metabolism of trypanosomatids, the causative agents of human African trypanosomiasis (HAT), Chagas’ disease, and leishmaniases. Introduction of a new, lean propargylic vector to a known class of TR inhibitors resulted in the strongest reported competitive inhibitor of Trypanosoma ( T .) brucei TR, with an inhibition constant K i of 73 n m , which is fully selective against human glutathione reductase (hGR). The best ligands exhibited in vitro IC 50 values (half‐maximal inhibitory concentration) against the HAT pathogen, T. brucei rhodesiense , in the mid‐nanomolar range, reaching down to 50 n m. X‐Ray co‐crystal structures confirmed the binding mode of the ligands and revealed the presence of a HEPES buffer molecule in the large active site. Extension of the propargylic vector, guided by structure‐based design, to replace the HEPES buffer molecule should give inhibitors with low nanomolar K i and IC 50 values for in vivo studies.