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3-aminopiperidine-based peptide analogues as the first selective noncovalent inhibitors of the bacterial cysteine protease IdeS
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
Vise andre og tillknytning
2012 (engelsk)Inngår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, nr 6, s. 2549-2560Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

sted, utgiver, år, opplag, sider
2012. Vol. 55, nr 6, s. 2549-2560
HSV kategori
Identifikatorer
URN: urn:nbn:se:umu:diva-55368DOI: 10.1021/jm201517aISI: 000301767000004OAI: oai:DiVA.org:umu-55368DiVA, id: diva2:529664
Tilgjengelig fra: 2012-05-31 Laget: 2012-05-14 Sist oppdatert: 2018-06-08bibliografisk kontrollert
Inngår i avhandling
1. Studies on secreted cysteine proteases of Streptococcus pyogenes: IdeS and SpeB
Åpne denne publikasjonen i ny fane eller vindu >>Studies on secreted cysteine proteases of Streptococcus pyogenes: IdeS and SpeB
2014 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

The pathogen Streptococcus pyogenes is a significant cause of human morbidity and mortality. Most of the work in this thesis is focused on streptococcal virulence factor IdeS, but the thesis also features work on SpeB, another streptococcal virulence factor. Both IdeS and SpeB are secreted cysteine proteases and both have previously been shown to degrade human IgG. IgG is the only known substrate for IdeS while SpeB is a more promiscuous protease with a larger number of identified substrates. A significant part of the data presented in this thesis is the result of designing and optimizing methods to detect and accurately measure the proteolytic degradation of IgG. Methods aimed at measuring the binding interactions between enzyme and substrate have also been frequently utilized. I show that IdeS is a monomeric protease, as opposed to previously published data that suggested it to be dimeric. IdeS cleaves the two heavy chains of IgG in a two-step reaction and I demonstrate that the first cleavage is magnitudes faster than the second one. This means that IdeS is a more efficient enzyme than previously thought. The difference in rate cannot completely be explained by a loss of affinity between IdeS and IgG after the cleavage of the first heavy chain. The velocity of IdeS is further increased by the presence of human Cystatin C, via an unknown mechanism. Cystatin C is normally a protease inhibitor and it having an opposite effect is puzzling.The synthesis and evaluation of novel inhibitors are also described. Peptide analogues mimicking the sequence surrounding the scissile bond on IgG - with an amino acid replaced with a more rigid motif - act as specific, but low-affinity, inhibitors of IdeS. The peptide analogues’ inhibitory capacity for SpeB and papain was also assayed.When it comes to SpeB, I show that it does not have IgG as a substrate under physiological conditions, in contrast to what was previously thought. This thesis does not only present findings on the IgG degrading capacity of IdeS and SpeB but also include data on fundamental enzymatic properties for these proteases.

sted, utgiver, år, opplag, sider
Umeå: Umeå Universitet, 2014. s. 49
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1646
Emneord
Streptococcus pyogenes, Group A Streptococci, GAS, virulence factor, IdeS, SpeB, cysteine protease, protease inhibitor, IgG, immune evasion
HSV kategori
Forskningsprogram
molekylär bioteknik (inst f molekylärbiologi)
Identifikatorer
urn:nbn:se:umu:diva-88223 (URN)978-91-7601-048-8 (ISBN)
Disputas
2014-05-27, Sal E04, by 6E, Norrlands universitetssjukhus, Umeå, 13:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2014-05-06 Laget: 2014-04-28 Sist oppdatert: 2018-06-07bibliografisk kontrollert

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