Format

Send to

Choose Destination
Cell Chem Biol. 2017 Dec 21;24(12):1523-1536.e4. doi: 10.1016/j.chembiol.2017.09.007. Epub 2017 Oct 26.

General and Modular Strategy for Designing Potent, Selective, and Pharmacologically Compliant Inhibitors of Rhomboid Proteases.

Author information

1
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo n. 2, Prague 166 10, Czech Republic; First Faculty of Medicine, Charles University, Kateřinská 32, Prague 121 08, Czech Republic.
2
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo n. 2, Prague 166 10, Czech Republic.
3
Medical Research Council Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.
4
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo n. 2, Prague 166 10, Czech Republic; Department of Genetics and Microbiology, Faculty of Science, Charles University, Viničná 5, Prague 128 44, Czech Republic.
5
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo n. 2, Prague 166 10, Czech Republic; Department of Biochemistry, Faculty of Science, Charles University, Hlavova 2030/8, Prague 128 43, Czech Republic.
6
Leibniz Institute for Analytical Sciences ISAS, Otto-Hahn-Strasse 6b, 44227 Dortmund, Germany.
7
Leibniz Institute for Analytical Sciences ISAS, Otto-Hahn-Strasse 6b, 44227 Dortmund, Germany; KU Leuven - University of Leuven, Herestraat 49, Box 802, 3000 Leuven, Belgium.
8
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 428, New York, NY 10065, USA.
9
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo n. 2, Prague 166 10, Czech Republic. Electronic address: kvido.strisovsky@uochb.cas.cz.

Abstract

Rhomboid-family intramembrane proteases regulate important biological processes and have been associated with malaria, cancer, and Parkinson's disease. However, due to the lack of potent, selective, and pharmacologically compliant inhibitors, the wide therapeutic potential of rhomboids is currently untapped. Here, we bridge this gap by discovering that peptidyl α-ketoamides substituted at the ketoamide nitrogen by hydrophobic groups are potent rhomboid inhibitors active in the nanomolar range, surpassing the currently used rhomboid inhibitors by up to three orders of magnitude. Such peptidyl ketoamides show selectivity for rhomboids, leaving most human serine hydrolases unaffected. Crystal structures show that these compounds bind the active site of rhomboid covalently and in a substrate-like manner, and kinetic analysis reveals their reversible, slow-binding, non-competitive mechanism. Since ketoamides are clinically used pharmacophores, our findings uncover a straightforward modular way for the design of specific inhibitors of rhomboid proteases, which can be widely applicable in cell biology and drug discovery.

KEYWORDS:

crystal structure; inhibition; inhibitor; intramembrane protease; ketoamide; mechanism; rhomboid protease; specificity

PMID:
29107700
PMCID:
PMC5746060
DOI:
10.1016/j.chembiol.2017.09.007
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center