Development of succinimide-based inhibitors for the mitochondrial rhomboid protease PARL
Abstract
While the biochemistry of rhomboid proteases has been extensively studied since their discovery two decades ago, efforts to define the physiological roles of these enzymes are ongoing and would benefit from chemical probes that can be used to manipulate the functions of these proteins in their native settings. Here, we describe the use of activity-based protein profiling (ABPP) technology to conduct a targeted screen for small-molecule inhibitors of the mitochondrial rhomboid protease PARL, which plays a critical role in regulating mitophagy and cell death. We synthesized a series of succinimide-containing sulfonyl esters and sulfonamides and discovered that these compounds serve as inhibitors of PARL with the most potent sulfonamides having submicromolar affinity for the enzyme. A counterscreen against the bacterial rhomboid protease GlpG demonstrates that several of these compounds display selectivity for PARL over GlpG by as much as two orders of magnitude. Both the sulfonyl ester and sulfonamide scaffolds exhibit reversible binding and are able to engage PARL in mammalian cells. Collectively, our findings provide encouraging precedent for the development of PARL-selective inhibitors and establish N-[(arylsulfonyl)oxy]succinimides and N-arylsulfonylsuccinimides as new molecular scaffolds for inhibiting members of the rhomboid protease family.
Repository Citation
Parsons, William H., Nicholas T. Rutland, Jennifer A. Crainic, et al. 2021. "Development of succinimide-based inhibitors for the mitochondrial rhomboid protease PARL." Bioorganic & Medicinal Chemistry Letters 49(1): 128290.
Publisher
Pergamon-Elsevier Science
Publication Date
10-1-2021
Publication Title
Bioorganic & Medicinal Chemistry Letters
Department
Chemistry and Biochemistry
Document Type
Article
DOI
https://dx.doi.org/10.1016/j.bmcl.2021.128290
Keywords
Activity-based protein profiling, Rhomboid protease, Protease inhibitor, Catalytic mechanism
Language
English
Format
text