The isoenzyme of glutaminyl cyclase is an important regulator of monocyte infiltration under inflammatory conditions

abstract: ...Acute and chronic inflammatory disorders are characterized by detrimental cytokine and chemokine expression. Frequently, the chemotactic activity of cytokines depends on a modified N-terminus of the polypeptide. Among those, the N-terminus of monocyte chemoattractant protein 1 (CCL2 and MCP-1) is modified to a pyroglutamate (pE-) residue protecting against degradation in vivo . Here, we show that the N-terminal pE-formation depends on glutaminyl cyclase activity. The pE-residue increases stability against N-terminal degradation by aminopeptidases and improves receptor activation and signal transduction in vitro . Genetic ablation of the glutaminyl cyclase iso-enzymes QC ( QPCT ) or isoQC ( QPCTL ) revealed a major role of isoQC for pE 1 -CCL2 formation and monocyte infiltration. Consistently, administration of QC-inhibitors in inflammatory models, such as thioglycollate-induced peritonitis reduced monocyte infiltration. The pharmacologic efficacy of QC/isoQC-inhibition was assessed in accelerated atherosclerosis in ApoE3*Leiden mice, showing attenuated atherosclerotic pathology following chronic oral treatment. Current strategies targeting CCL2 are mainly based on antibodies or spiegelmers. The application of small, orally available inhibitors of glutaminyl cyclases represents an alternative therapeutic strategy to treat CCL2-driven disorders such as atherosclerosis/restenosis and fibrosis.

...EMBO Mol Med EMBO Mol Med emmm EMBO Molecular Medicine 1757-4676 1757-4684 WILEY-VCH Verlag Weinheim 21774078 3377097 10.1002/emmm.201100158 Research Article The isoenzyme of glutaminyl cyclase is an important regulator of monocyte infiltration under inflammatory conditions Cynis Holger 1 Hoffmann Torsten 1 Friedrich Daniel 1 Kehlen Astrid 1 Gans Kathrin 1 Kleinschmidt Martin 1 Rahfeld Jens-Ulrich 1 Wolf Raik 1 Wermann Michael 1 Stephan Anett 1 Haegele Monique 1 Sedlmeier Reinhard 2 Graubner Sigrid 2 Jagla Wolfgang 2 Mller Anke 2 Eichentopf Rico 1 Heiser Ulrich 1 Seifert Franziska 3 Quax Paul H A 4 de Vries Margreet R 4 Hesse Isabel 5 Trautwein Daniela 5 Wollert Ulrich 5 Berg Sabine 6 Freyse Ernst-Joachim 6 Schilling Stephan 1 * Demuth Hans-Ulrich 1 2 1 Probiodrug AG Halle, Germany 2 Ingenium Pharmaceuticals GmbH Martinsried, Germany 3 Albrecht-von-Haller-Institute, Georg-August University Gttingen, Germany 4 Department of Vascular Surgery, Leiden University Medical Center Leiden, The Netherlands 5 Department for Vascular Surgery, St. Elisabeth and St. Barbara Hospital Halle, Germany 6 Institute of Diabetes Karlsburg, Germany * Corresponding author: Tel: +49 345 555 99 11, Fax: +49 345 555 99 01; E-mail: stephan.schilling@probiodrug.de 9 2011 3 9 545 558 18 3 2011 01 6 2011 08 6 2011 Copyright 2011 EMBO Molecular Medicine 2011 Acute and chronic inflammatory disorders are characterized by detrimental cytokine and chemokine expression. Frequently, the chemotactic activity of cytokines depends on a modified N-terminus of the polypeptide. Among those, the N-terminus of monocyte chemoattractant protein 1 (CCL2 and MCP-1) is modified to a pyroglutamate (pE-) residue protecting against degradation in vivo . Here, we show that the N-terminal pE-formation depends on glutaminyl cyclase activity. The pE-residue increases stability against N-terminal degradation by aminopeptidases and improves receptor activation and signal transduction in vitro . Genetic ablation of the glutaminyl cyclase iso-enzymes QC ( QPCT ) or isoQC ( QPCTL ) revealed a major role of isoQC for pE 1 -CCL2 formation and monocyte infiltration. Consistently, administration of QC-inhibitors in inflammatory models, such as thioglycollate-induced peritonitis reduced monocyte infiltration. The pharmacologic efficacy of QC/isoQC-inhibition was assessed in accelerated atherosclerosis in ApoE3*Leiden mice, showing attenuated atherosclerotic pathology following chronic oral treatment. Current strategies targeting CCL2 are mainly based on antibodies or spiegelmers. The application of small, orally available inhibitors of glutaminyl cyclases represents an alternative therapeutic strategy to treat CCL2-driven disorders such as atherosclerosis/restenosis and fibrosis. CCL2 drug development glutaminyl cyclases inflammation pyroglutamate See accompanying article http://dx.doi.org/10.1002/emmm.201100161 INTRODUCTION CCL2 plays a pivotal role in different inflammatory disorders such as atherosclerosis (Charo & Taubman, 2004

... modification has been linked to increased resistance against degradation and enhanced aggregation propensity (Schilling et al, 2008 ). Likewise, also for the MCPs a protecting function has been suggested (Van Damme et al, 1999 ), which, in turn, stabilizes chemotactic activity. The N-terminal pE is post-translationally formed from a glutaminyl precursor by glutaminyl cyclase (E.C. 2.3.2.5, QPCT , QC; Fischer & Spiess, 1987 ; Schilling et al, 2003 ) or iso-glutaminyl cyclase (E.C. 2.3.2.5, QPCTL , isoQC

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Gene: QPCTL - glutaminyl-peptide cyclotransferase-like - (NCBI)

Protein : 3pb7

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