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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F17%3A00100111" target="_blank" >RIV/00216224:14740/17:00100111 - isvavai.cz</a>

Výsledek na webu

<a href="http://science.sciencemag.org/content/355/6332/1416" target="_blank" >http://science.sciencemag.org/content/355/6332/1416</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1126/science.aal1807" target="_blank" >10.1126/science.aal1807</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10600 - Biological sciences

Projekt

<a href="/cs/project/LQ1601" target="_blank" >LQ1601: CEITEC 2020</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2017

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Science

ISSN

0036-8075

e-ISSN

—

Svazek periodika

355

Číslo periodika v rámci svazku

6332

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

5

Strana od-do

1416

Kód UT WoS článku

000397809500041

EID výsledku v databázi Scopus

2-s2.0-85016811904