4-Oxo-β-lactams as Covalent Inhibitors of the Mitochondrial Intramembrane Protease PARL Rhomboid proteases play a variety of physiological roles, but rhomboid protease inhibitors have been mostly developed for the E. coli model rhomboid GlpG. In this work, we screened different electrophilic scaffolds against the human mitochondrial rhomboid PARL and found 4-oxo-β-lactams as submicromolar inhibitors. Multifaceted computations suggest explanations for the activity at the molecular scale and provide models of covalently bound complexes. Together with the straightforward synthesis of the 4-oxo-β-lactam scaffold, this may pave the way toward selective, nonpeptidic PARL inhibitors.

#research #RhomboidProteases

4-Oxo-β-lactams as Covalent Inhibitors of the Mitochondrial Intramembrane Protease PARL (Strisovsky, VerhelstLab) - ACS Med. Chem. Lett.: doi.org/10.1021/acsm...

#KU_Leuven @iocbprague.bsky.social @czechacademy.bsky.social

#research

Extensive targeting of chemical space at the prime side of #KetoamideInhibitors of #RhomboidProteases by branched substituents empowers their selectivity and potency (Strisovsky) - Eur. J. Med. Chem.: doi.org/10.1016/j.ej...

@iocbprague.bsky.social

Exciting news by Lange Lab & @HanSun_Lab on #RhomboidProteases. Our study @ScienceAdvances sheds light on their gate dynamics, helping understand roles in diseases like cancer & Parkinson's & sees potential in them as therapeutic targets. #nmr 👉https://t.co/x9Q73y60ud