title: Selectivity profiling of DegP substrates and inhibitors.
abstract: Protein quality control factors are involved in many key physiological processes and severe human diseases that are based on misfolding or amyloid formation. Prokaryotic representatives are often virulence factors of pathogenic bacteria. Therefore, protein quality control factors represent a novel class of drug targets. The bacterial serine protease DegP, belonging to the widely conserved family of HtrA proteases, exhibits unusual structural and functional plasticity that could be exploited by small molecule modulators. However, only one weak synthetic peptide substrate and no inhibitors are available to date. We report the identification of a potent heptameric pNA-substrate and chloromethyl ketone based inhibitors of DegP. In addition, specificity profiling resulted in the identification of one strong inhibitor and a potent substrate for subtilisin as well as a number of specific elastase substrates and inhibitors.
authors.affiliation: Chemical Genomics Centre der Max-Planck-Gesellschaft, Otto-Hahn-Str. 15, D-44227 Dortmund, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hauske
authors.forename: Michael
authors.initials: M
authors.lastname: Meltzer
authors.forename: Christian
authors.initials: C
authors.lastname: Ottmann
authors.forename: Tobias
authors.initials: T
authors.lastname: Krojer
authors.forename: Tim
authors.initials: T
authors.lastname: Clausen
authors.forename: Michael
authors.initials: M
authors.lastname: Ehrmann
authors.forename: Markus
authors.initials: M
authors.lastname: Kaiser
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000595:Amino Acid Sequence; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D033903:Periplasmic Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000814:Aniline Compounds; D006360:Heat-Shock Proteins; D010455:Peptides; D033903:Periplasmic Proteins; D011480:Protease Inhibitors; C019498:4-nitroaniline; C061682:DegP protease; D012697:Serine Endopeptidases