Details
| Originalsprache | Englisch |
|---|---|
| Seiten (von - bis) | 847-879 |
| Seitenumfang | 33 |
| Fachzeitschrift | Journal of medicinal chemistry |
| Jahrgang | 63 |
| Ausgabenummer | 2 |
| Publikationsstatus | Veröffentlicht - 20 Dez. 2019 |
Abstract
Trypanosoma protists are pathogens leading to a spectrum of devastating infectious diseases. The range of available chemotherapeutics against Trypanosoma is limited, and the existing therapies are partially ineffective and cause serious adverse effects. Formation of the PEX14-PEX5 complex is essential for protein import into the parasites' glycosomes. This transport is critical for parasite metabolism and failure leads to mislocalization of glycosomal enzymes, with fatal consequences for the parasite. Hence, inhibiting the PEX14-PEX5 protein-protein interaction (PPI) is an attractive way to affect multiple metabolic pathways. Herein, we have used structure-guided computational screening and optimization to develop the first line of compounds that inhibit PEX14-PEX5 PPI. The optimization was driven by several X-ray structures, NMR binding data, and molecular dynamics simulations. Importantly, the developed compounds show significant cellular activity against Trypanosoma, including the human pathogen Trypanosoma brucei gambiense and Trypanosoma cruzi parasites.
ASJC Scopus Sachgebiete
- Biochemie, Genetik und Molekularbiologie (insg.)
- Molekularmedizin
- Pharmakologie, Toxikologie und Pharmazie (insg.)
- Wirkstoffforschung
Ziele für nachhaltige Entwicklung
Zitieren
- Standard
- Harvard
- Apa
- Vancouver
- BibTex
- RIS
in: Journal of medicinal chemistry, Jahrgang 63, Nr. 2, 20.12.2019, S. 847-879.
Publikation: Beitrag in Fachzeitschrift › Artikel › Forschung › Peer-Review
}
TY - JOUR
T1 - Structure-Activity Relationship in Pyrazolo[4,3- c]pyridines, First Inhibitors of PEX14-PEX5 Protein-Protein Interaction with Trypanocidal Activity
AU - Dawidowski, Maciej
AU - Kalel, Vishal C.
AU - Napolitano, Valeria
AU - Fino, Roberto
AU - Schorpp, Kenji
AU - Emmanouilidis, Leonidas
AU - Lenhart, Dominik
AU - Ostertag, Michael
AU - Kaiser, Marcel
AU - Kolonko, Marta
AU - Tippler, Bettina
AU - Schliebs, Wolfgang
AU - Dubin, Grzegorz
AU - Mäser, Pascal
AU - Tetko, Igor V.
AU - Hadian, Kamyar
AU - Plettenburg, Oliver
AU - Erdmann, Ralf
AU - Sattler, Michael
AU - Popowicz, Grzegorz M.
PY - 2019/12/20
Y1 - 2019/12/20
N2 - Trypanosoma protists are pathogens leading to a spectrum of devastating infectious diseases. The range of available chemotherapeutics against Trypanosoma is limited, and the existing therapies are partially ineffective and cause serious adverse effects. Formation of the PEX14-PEX5 complex is essential for protein import into the parasites' glycosomes. This transport is critical for parasite metabolism and failure leads to mislocalization of glycosomal enzymes, with fatal consequences for the parasite. Hence, inhibiting the PEX14-PEX5 protein-protein interaction (PPI) is an attractive way to affect multiple metabolic pathways. Herein, we have used structure-guided computational screening and optimization to develop the first line of compounds that inhibit PEX14-PEX5 PPI. The optimization was driven by several X-ray structures, NMR binding data, and molecular dynamics simulations. Importantly, the developed compounds show significant cellular activity against Trypanosoma, including the human pathogen Trypanosoma brucei gambiense and Trypanosoma cruzi parasites.
AB - Trypanosoma protists are pathogens leading to a spectrum of devastating infectious diseases. The range of available chemotherapeutics against Trypanosoma is limited, and the existing therapies are partially ineffective and cause serious adverse effects. Formation of the PEX14-PEX5 complex is essential for protein import into the parasites' glycosomes. This transport is critical for parasite metabolism and failure leads to mislocalization of glycosomal enzymes, with fatal consequences for the parasite. Hence, inhibiting the PEX14-PEX5 protein-protein interaction (PPI) is an attractive way to affect multiple metabolic pathways. Herein, we have used structure-guided computational screening and optimization to develop the first line of compounds that inhibit PEX14-PEX5 PPI. The optimization was driven by several X-ray structures, NMR binding data, and molecular dynamics simulations. Importantly, the developed compounds show significant cellular activity against Trypanosoma, including the human pathogen Trypanosoma brucei gambiense and Trypanosoma cruzi parasites.
UR - http://www.scopus.com/inward/record.url?scp=85078521664&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.9b01876
DO - 10.1021/acs.jmedchem.9b01876
M3 - Article
C2 - 31860309
AN - SCOPUS:85078521664
VL - 63
SP - 847
EP - 879
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
SN - 0022-2623
IS - 2
ER -