| DAWIDOWSKI, M., L. EMMANOUILIDIS, V.C. KALEL, Konstantinos TRIPSIANES, K. SCHORPP, K. HADIAN, M. KAISER, P. MASER, M. KOLONKO, S. TANGHE, A. RODRIGUEZ, W. SCHLIEBS, R. ERDMANN, M. SATTLER a G.M. POPOWICZ. Inhibitors of PEX14 disrupt protein import into glycosomes and kill Trypanosoma parasites. Science. WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE, 2017, roč. 355, č. 6332, s. 1416-1420. ISSN 0036-8075. Dostupné z: https://dx.doi.org/10.1126/science.aal1807. |
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@article{1409392,
author = {Dawidowski, M. and Emmanouilidis, L. and Kalel, V.C. and Tripsianes, Konstantinos and Schorpp, K. and Hadian, K. and Kaiser, M. and Maser, P. and Kolonko, M. and Tanghe, S. and Rodriguez, A. and Schliebs, W. and Erdmann, R. and Sattler, M. and Popowicz, G.M.},
article_location = {WASHINGTON},
article_number = {6332},
doi = {http://dx.doi.org/10.1126/science.aal1807},
keywords = {DRUG-RESISTANCE; CHAGAS-DISEASE; RECEPTORS PEX5; PEROXISOMES; BRUCEI; CRUZI; COMPARTMENTATION; MAINTENANCE; HEXOKINASE; GLYCOLYSIS},
language = {eng},
issn = {0036-8075},
journal = {Science},
title = {Inhibitors of PEX14 disrupt protein import into glycosomes and kill Trypanosoma parasites},
url = {http://science.sciencemag.org/content/355/6332/1416},
volume = {355},
year = {2017}
}
TY - JOUR
ID - 1409392
AU - Dawidowski, M. - Emmanouilidis, L. - Kalel, V.C. - Tripsianes, Konstantinos - Schorpp, K. - Hadian, K. - Kaiser, M. - Maser, P. - Kolonko, M. - Tanghe, S. - Rodriguez, A. - Schliebs, W. - Erdmann, R. - Sattler, M. - Popowicz, G.M.
PY - 2017
TI - Inhibitors of PEX14 disrupt protein import into glycosomes and kill Trypanosoma parasites
JF - Science
VL - 355
IS - 6332
SP - 1416
EP - 1416
PB - AMER ASSOC ADVANCEMENT SCIENCE
SN - 00368075
KW - DRUG-RESISTANCE
KW - CHAGAS-DISEASE
KW - RECEPTORS PEX5
KW - PEROXISOMES
KW - BRUCEI
KW - CRUZI
KW - COMPARTMENTATION
KW - MAINTENANCE
KW - HEXOKINASE
KW - GLYCOLYSIS
UR - http://science.sciencemag.org/content/355/6332/1416
L2 - http://science.sciencemag.org/content/355/6332/1416
N2 - The parasitic protists of the Trypanosoma genus infect humans and domestic mammals, causing severe mortality and huge economic losses. The most threatening trypanosomiasis is Chagas disease, affecting up to 12 million people in the Americas. We report a way to selectively kill Trypanosoma by blocking glycosomal/peroxisomal import that depends on the PEX14-PEX5 protein-protein interaction. We developed small molecules that efficiently disrupt the PEX14-PEX5 interaction. This results in mislocalization of glycosomal enzymes, causing metabolic catastrophe, and it kills the parasite. High-resolution x-ray structures and nuclear magnetic resonance data enabled the efficient design of inhibitors with trypanocidal activities comparable to approved medications. These results identify PEX14 as an "Achilles' heel" of the Trypanosoma suitable for the development of new therapies against trypanosomiases and provide the structural basis for their development.
ER -
DAWIDOWSKI, M., L. EMMANOUILIDIS, V.C. KALEL, Konstantinos TRIPSIANES, K. SCHORPP, K. HADIAN, M. KAISER, P. MASER, M. KOLONKO, S. TANGHE, A. RODRIGUEZ, W. SCHLIEBS, R. ERDMANN, M. SATTLER a G.M. POPOWICZ. Inhibitors of PEX14 disrupt protein import into glycosomes and kill Trypanosoma parasites. \textit{Science}. WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE, 2017, roč.~355, č.~6332, s.~1416-1420. ISSN~0036-8075. Dostupné z: https://dx.doi.org/10.1126/science.aal1807.
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