5L87

Targeting the PEX14-PEX5 interaction by small molecules provides novel therapeutic routes to treat trypanosomiases.

Summary for 5L87

• Entry DOI: 10.2210/pdb5l87/pdb
• Related: 2W84
• Descriptor: Peroxin 14, 5-(1~{H}-indol-3-ylmethyl)-1-methyl-~{N}-(naphthalen-1-ylmethyl)-6,7-dihydro-4~{H}-pyrazolo[4,3-c]pyridine-3-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: trypanosomiasis, glycosome, protein-protein interaction inhibitor, structure-based drug discovery, inhibitor, membrane protein
• Biological source: Trypanosoma brucei brucei
• Total number of polymer chains: 1
• Total formula weight: 8394.69

Authors

Dawidowski, M.,Emmanouilidis, L.,Sattler, M.,Popowicz, G.M. (deposition date: 2016-06-07, release date: 2017-03-08, Last modification date: 2024-01-10)

Primary citation

Dawidowski, M.,Emmanouilidis, L.,Kalel, V.C.,Tripsianes, K.,Schorpp, K.,Hadian, K.,Kaiser, M.,Maser, P.,Kolonko, M.,Tanghe, S.,Rodriguez, A.,Schliebs, W.,Erdmann, R.,Sattler, M.,Popowicz, G.M.
Inhibitors of PEX14 disrupt protein import into glycosomes and kill Trypanosoma parasites.
Science, 355:1416-1420, 2017

PubMed Abstract: The parasitic protists of the 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 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 suitable for the development of new therapies against trypanosomiases and provide the structural basis for their development.

PubMed: 28360328
DOI: 10.1126/science.aal1807

Experimental method

X-RAY DIFFRACTION (0.87 Å)