jm201517a_si_001.pdf (811.96 kB)
3-Aminopiperidine-Based Peptide Analogues as the First Selective Noncovalent Inhibitors of the Bacterial Cysteine Protease IdeS
journal contribution
posted on 2015-12-16, 21:11 authored by Kristina Berggren, Reine Vindebro, Claes Bergström, Christian Spoerry, Helena Persson, Tomas Fex, Jan Kihlberg, Ulrich von Pawel-Rammingen, Kristina LuthmanA 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.