title: 3-aminopiperidine-based peptide analogues as the first selective noncovalent inhibitors of the bacterial cysteine protease IdeS.
abstract: A series of eight peptides corresponding to the amino acid sequence of the hinge region of IgG and 17 newly synthesized peptide analogues containing a piperidine moiety as a replacement of a glycine residue were tested as potential inhibitors of the bacterial IgG degrading enzyme of  Streptococcus pyogenes , IdeS. None of the peptides showed any inhibitory activity of IdeS, but several piperidine-based analogues were identified as inhibitors. Two different analysis methods were used: an SDS-PAGE based assay to detect IgG cleavage products and a surface plasmon resonance spectroscopy based assay to quantify the degree of inhibition. To investigate the selectivity of the inhibitors for IdeS, all compounds were screened against two other related cysteine proteases (SpeB and papain). The selectivity results show that larger analogues that are active inhibitors of IdeS are even more potent as inhibitors of papain, whereas smaller analogues that are active inhibitors of IdeS inhibit neither SpeB nor papain. Two compounds were identified that exhibit high selectivity against IdeS and will be used for further studies.
authors.affiliation: Department of Chemistry, Medicinal Chemistry, University of Gothenburg, SE-412 96 Göteborg, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Berggren
authors.forename: Reine
authors.initials: R
authors.lastname: Vindebro
authors.forename: Claes
authors.initials: C
authors.lastname: Bergström
authors.forename: Christian
authors.initials: C
authors.lastname: Spoerry
authors.forename: Helena
authors.initials: H
authors.lastname: Persson
authors.forename: Tomas
authors.initials: T
authors.lastname: Fex
authors.forename: Jan
authors.initials: J
authors.lastname: Kihlberg
authors.forename: Ulrich
authors.initials: U
authors.lastname: von Pawel-Rammingen
authors.forename: Kristina
authors.initials: K
authors.lastname: Luthman
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D004591:Electrophoresis, Polyacrylamide Gel; D057075:Enzyme Assays; D005098:Exotoxins / Q000037:antagonists & inhibitors / Q000737:chemistry; D007074:Immunoglobulin G / Q000737:chemistry*; D008969:Molecular Sequence Data; D010206:Papain / Q000037:antagonists & inhibitors / Q000737:chemistry; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013297:Streptococcus pyogenes / Q000201:enzymology; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D015853:Cysteine Proteinase Inhibitors; D005098:Exotoxins; D007074:Immunoglobulin G; C442815:Mac-1-like protein, Streptococcus; D057786:Peptidomimetics; D010880:Piperidines; C027951:erythrogenic toxin; D010206:Papain