Inhibitors of PEX14 disrupt protein import into glycosomes and
kill Trypanosoma parasites

J 2017

Inhibitors of PEX14 disrupt protein import into glycosomes and kill Trypanosoma parasites

DAWIDOWSKI, M.; L. EMMANOUILIDIS; V.C. KALEL; Konstantinos TRIPSIANES; K. SCHORPP et al.

Základní údaje

Originální název

Inhibitors of PEX14 disrupt protein import into glycosomes and kill Trypanosoma parasites

Autoři

Vydání

Science, WASHINGTON, AMER ASSOC ADVANCEMENT SCIENCE, 2017, 0036-8075

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10600 1.6 Biological sciences

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 41.058

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14740/17:00100111

Organizační jednotka

Středoevropský technologický institut

Klíčová slova anglicky

DRUG-RESISTANCE; CHAGAS-DISEASE; RECEPTORS PEX5; PEROXISOMES; BRUCEI; CRUZI; COMPARTMENTATION; MAINTENANCE; HEXOKINASE; GLYCOLYSIS

Štítky

rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 13. 3. 2018 12:11, Mgr. Pavla Foltynová, Ph.D.

Anotace

V originále

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.

Návaznosti

LQ1601, projekt VaV

Název: CEITEC 2020 (Akronym: CEITEC2020)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CEITEC 2020

Citovat

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://doi.org/10.1126/science.aal1807.

@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 = {https://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://doi.org/10.1126/science.aal1807.

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