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Pyroglutamated Aß and Neuroinflammation: Targeting fundamentals of AD pathogenesis by QC inhibition.
Halle / Saale, July 11, 2009 — Probiodrug AG (Probiodrug), a developer of small molecule inhibitors for the treatment of neurodegenerative and inflammatory diseases, announced today that the company will present an update on its human glutaminyl cyclase inhibition program for the treatment of Alzheimer’s disease (AD) at the ICAD 2009 in Vienna, Austria, July 11-16.
During the conference, in two different sessions, on Sunday
(F1-02 N-Terminally Modified Abeta –
Emerging Target in Alzheimer’s Disease Therapy) and Tuesday
(S3-02 Animal and Cellular Models) Probiodrug will present the company’s progress in validation of human glutam(in)yl cyclase (QC) enzymes as a target for treatment Alzheimer’s disease and neuroinflammation.
Probiodrug`s studies provide strong evidence for a glutaminyl cyclase (QC, EC 2.3.2.5) catalyzed cyclization of N-terminal glutamine or glutamic acid residues of peptides. The reactions are either crucial for maturation of pro-inflammatory cytokines like MCP-1, or for formation of pGlu-modified amyloid peptides in neurodegenerative amyloidoses like AD and familial dementias. Pyroglutamate (pGlu)-modified Aß peptides are major constituents of plaques in AD. Formation of pGlu at the N-terminus of Aß decreases its solubility, which, in turn, accelerates Aß aggregate formation. Moreover, pGlu-Aß confers resistance against protease cleavage. Interestingly, the appearance of pGlu-Aß apparently coincides with an upregulation of QC in AD.
To evaluate the role of pGlu-Aß, a QC-inhibitor was applied orally to mouse models with AD-like pathology for different durations under prophylactic and therapeutic conditions. In both, the prophylactic and therapeutic studies, a dose-dependent reduction of pGlu-Aß was observed, which was also accompanied by a dose-dependent decrease of amyloid plaques and by improvements of spatial and contextual fear memory.
Summarizing, the catalytic feature of QC to provoke the N-terminal pGlu-formation from glutamine and glutamic acid with significant proficiency, suggests a crucial role of the enzyme for the formation of N-terminally pyroglutamated amyloid peptides. The accumulation of these degradation-resistant peptides with a high propensity for aggregation influences the amyloid-plaque formation /stabilization and likely influences the toxicity of Aß, as also suggested by Probiodrug`s novel transgenic mouse models. Thus, inhibition of glutaminyl cyclase represents a novel approach to interfere with amyloid-driven neurodegeneration in disorders with enhanced production of pGlu-modified peptides.
About Probiodrug AG:
Probiodrug is a biopharmaceutical company specialized on the development of innovative small molecule drugs for the treatment of neuronal, inflammatory, and autoimmune diseases. In these areas, Probiodrug is focusing on innovative targets with the prospect of first and best in class therapeutics.
Contact:
Dr Konrad Glund, CEO
Probiodrug AG
Weinbergweg 22
D-06120 Halle/ Saale
Germany
Tel.: +49 345 55599-00
Fax: +49 345 55599-01
Mail: konrad.glund@probiodrug.de
Dr Ludger Weß
akampion
Saseler Loge 6b
D-22393 Hamburg
Germany Tel.: +49 40 88 16 59 64
Fax: +49 40 88 16 59 65
Mail: ludger@akampion.com