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.

Stable and Functional Rhomboid Proteases in Lipid Nanodiscs by Using Diisobutylene/Maleic Acid Copolymers

“…The biological roles of rhomboid proteases are diverse and range from EGF signaling − to quorum sensing . Rhomboid proteases have also been implied in human disease, including Parkinson’s disease , and malaria. , Structurally, they are the best characterized IMPs, ,, and a variety of different rhomboid inhibitor scaffolds have been reported. − …”

Tailored Ahp‐cyclodepsipeptides as Potent Non‐covalent Serine Protease Inhibitors

“…[1] In contrast to the design of covalent inhibitors or activity-based probes for this enzyme class, [2] generic approaches for designing potent, enzyme-class-specific,c ellactive,and non-covalent small-molecule inhibitors are highly limited and have been achieved only for distinct serine proteases. [3] Consequently,a lternative approaches for the systematic generation of such chemical probes are urgently required.…”

Rapid synthesis of internal peptidyl α-ketoamides by on resin oxidation for the construction of rhomboid protease inhibitors

“…In the past decade, various electrophiles have been reported as scaffolds for the design and synthesis of rhomboid inhibitors. 7 These include 4-chloro-isocoumarins, 8,9 such as compound 1, b-lactams, e.g. compound 2, 10,11 benzoxazinones including compound 3, 12 and uorophosphonates such as compound 4 (ref.…”

“…(A) 4-chloro-isocoumarins (1), b-lactams (2), benzoxazinones (3) and fluorophosphonates (4). (B) a-Ketoamide rhomboid inhibitors(5)(6)(7). The peptidic element in the non-primed site is indicated with the P1-P4 position according to the Schechter and Berger protease substrate nomenclature 16.…”