title: Inhibitors of rhomboid proteases.
abstract: Rhomboid proteases form one of the most widespread families of intramembrane proteases. They utilize a catalytic serine-histidine dyad located several Å below the surface of the membrane for substrate hydrolysis. Multiple studies have implicated rhomboid proteases in biologically and medically relevant processes. Several assays have been developed that are able to monitor rhomboid activity. With the aid of these assays, different types of inhibitors have been found, all based on electrophiles that covalently react with the active site machinery. Although the currently available inhibitors have limited selectivity and moderate potency, they can function as research tools and as starting point for the development of activity-based probes, which are reagents that can specifically detect active rhomboid species. Structural studies on complexes of inhibitors with the Escherichia coli rhomboid GlpG have provided insight into how substrate recognition may occur. Future synthetic efforts, aided by high-throughput screening or structure-based design, may lead to more potent and selective inhibitors for this interesting family of proteases.
authors.affiliation: Chair for Chemistry of Biopolymers, Technische Universität München, Weihenstephaner Berg 3, 85354 Freising, Germany.
authors.forename: Eliane V
authors.initials: EV
authors.lastname: Wolf
authors.affiliation: Leibniz Institute for Analytical Sciences ISAS, e.V., Otto-Hahn-Str. 6b, 44227 Dortmund, Germany; Laboratory of Chemical Biology, Department of Cellular and Molecular Medicine, University of Leuven, Herestr. 49, 3000 Leuven, Belgium. Electronic address: steven.verhelst@kuleuven.be.
authors.forename: Steven H L
authors.initials: SH
authors.lastname: Verhelst
mesh_terms: D055162:Biocatalysis / Q000187:drug effects; D020134:Catalytic Domain; D055808:Drug Discovery / Q000379:methods; D008958:Models, Molecular; D015394:Molecular Structure; D010447:Peptide Hydrolases / Q000737:chemistry* / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D011480:Protease Inhibitors; D010447:Peptide Hydrolases
keywords: Activity-based probes; Inhibitors; Intramembrane proteases; Rhomboids