Informace o publikaci

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

Autoři	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.
Rok publikování	2017
Druh	Článek v odborném periodiku
Časopis / Zdroj	Science
Fakulta / Pracoviště MU	Středoevropský technologický institut
Citace
www	http://science.sciencemag.org/content/355/6332/1416
Doi	http://dx.doi.org/10.1126/science.aal1807
Klíčová slova	DRUG-RESISTANCE; CHAGAS-DISEASE; RECEPTORS PEX5; PEROXISOMES; BRUCEI; CRUZI; COMPARTMENTATION; MAINTENANCE; HEXOKINASE; GLYCOLYSIS
Popis	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.
Související projekty:	CEITEC 2020