Extensive targeting of chemical space at the prime side of ketoamide inhibitors of rhomboid proteases by branched substituents empowers their selectivity and potency.

Autor: Bach K; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic; Department of Molecular Genetics, Faculty of Science, Charles University, Viničná 5, Prague, 128 44, Czech Republic., Dohnálek J; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic; University of Chemistry and Technology, Technická 5, Prague, 166 28, Czech Republic., Škerlová J; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic., Kuzmík J; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic., Poláchová E; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic; First Faculty of Medicine, Charles University, Kateřinská 32, Prague, 121 08, Czech Republic., Stanchev S; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic., Majer P; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic., Fanfrlík J; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic., Pecina A; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic., Řezáč J; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic., Lepšík M; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic., Borshchevskiy V; Institute of Biological Information Processing 7, IBI-7 (Structural Biochemistry) Forschungszentrum Jülich 52428 Jülich, Germany., Polovinkin V; ELI Beamlines Centre, ELI ERIC, Za Radnicí 835, 252 41, Dolní Břežany, Czech Republic., Strisovsky K; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague, 160 00, Czech Republic. Electronic address: kvido.strisovsky@uochb.cas.cz.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Sep 05; Vol. 275, pp. 116606. Date of Electronic Publication: 2024 Jun 17.
DOI: 10.1016/j.ejmech.2024.116606
Abstrakt: Rhomboid intramembrane serine proteases have been implicated in several pathologies, and emerge as attractive pharmacological target candidates. The most potent and selective rhomboid inhibitors available to date are peptidyl α-ketoamides, but their selectivity for diverse rhomboid proteases and strategies to modulate it in relevant contexts are poorly understood. This gap, together with the lack of suitable in vitro models, hinders ketoamide development for relevant eukaryotic rhomboid enzymes. Here we explore the structure-activity relationship principles of rhomboid inhibiting ketoamides by medicinal chemistry and enzymatic in vitro and in-cell assays with recombinant rhomboid proteases GlpG, human mitochondrial rhomboid PARL and human RHBDL2. We use X-ray crystallography in lipidic cubic phase to understand the binding mode of one of the best ketoamide inhibitors synthesized here containing a branched terminal substituent bound to GlpG. In addition, to extend the interpretation of the co-crystal structure, we use quantum mechanical calculations and quantify the relative importance of interactions along the inhibitor molecule. These combined experimental analyses implicates that more extensive exploration of chemical space at the prime side is unexpectedly powerful for the selectivity of rhomboid inhibiting ketoamides. Together with variations in the peptide sequence at the non-prime side, or its non-peptidic alternatives, this strategy enables targeted tailoring of potent and selective ketoamides towards diverse rhomboid proteases including disease-relevant ones such as PARL and RHBDL2.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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