Inhibitors of PEX14 disrupt protein import into glycosomes and kill Trypanosoma parasites.
Science
; 355(6332): 1416-1420, 2017 03 31.
Article
in En
| MEDLINE
| ID: mdl-28360328
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Health context:
3_ND
Database:
MEDLINE
Main subject:
Trypanocidal Agents
/
Trypanosoma brucei brucei
/
Protozoan Proteins
/
Small Molecule Libraries
/
Membrane Proteins
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Science
Year:
2017
Document type:
Article