Journal article
Authors list: Andricopulo, AD; Akoachere, MB; Krogh, R; Nickel, C; McLeish, MJ; Kenyon, GL; Arscott, LD; Williams, CH; Davioud-Charvet, E; Becker, K
Publication year: 2006
Pages: 2283-2292
Journal: Bioorganic & Medicinal Chemistry Letters
Volume number: 16
Issue number: 8
ISSN: 0960-894X
DOI Link: https://doi.org/10.1016/j.bmcl.2006.01.027
Publisher: Elsevier
Abstract:
Plasmodium falciparum thioredoxin reductase (PfTrxR:NADPH+Trx(S)(2)+H+<-> NADP(+)+Trx(SH)(2)) is a high M-r flavin-dependent TrxR that reduces thioredoxin (Trx) via a CysXXXXCys pair located penultimately to the C-terminal Gly. In this respect, PfTrxR differs significantly from its human counterpart which bears a Cys-Sec redox pair at the same position. PfTrxR is essentially involved in antioxidant defense and redox regulation of the parasite and has been previously validated by knock-out studies as a potential drug target for malaria chemotherapy. Moreover, human TrxR is present in most cancer cells at levels tenfold higher than in normal cells. Here we report the discovery of a series of potent inhibitors of PfTrxR. The three most promising inhibitors, 3 (IC50PfTrxR=2 mu M and IC50hTrxR=50 mu M), 7 (IC50PfTrxR=2 mu M and IC50hTrxR=140 mu M), and 11 (IC50PfTrxR=0.5 mu M and IC50hTrxR=4 mu M) were selective for the parasite enzyme. Detailed mechanistic characterization of the effects of these compounds on the PfTrxR-catalyzed reaction showed clear uncompetitive inhibition with respect to both substrate and cofactor. For the most specific PfTrxR inhibitor 7, an alkylation mechanism study based oil a thiol conjugation model was performed. Furthermore, all three compounds were active in the lower micromolar range on the chloroquine-resistant P. falciparum strain K1 in vitro. (C) 2006 Elsevier Ltd. All rights reserved.
Citation Styles
Harvard Citation style: Andricopulo, A., Akoachere, M., Krogh, R., Nickel, C., McLeish, M., Kenyon, G., et al. (2006) Specific inhibitors of Plasmodium falciparum thioredoxin reductase as potential antimalarial agents, Bioorganic & Medicinal Chemistry Letters, 16(8), pp. 2283-2292. https://doi.org/10.1016/j.bmcl.2006.01.027
APA Citation style: Andricopulo, A., Akoachere, M., Krogh, R., Nickel, C., McLeish, M., Kenyon, G., Arscott, L., Williams, C., Davioud-Charvet, E., & Becker, K. (2006). Specific inhibitors of Plasmodium falciparum thioredoxin reductase as potential antimalarial agents. Bioorganic & Medicinal Chemistry Letters. 16(8), 2283-2292. https://doi.org/10.1016/j.bmcl.2006.01.027
