Inhibition of human glutaminyl cyclase: A potential new treatment for AD

MEDI 460

Ulrich Heiser, ulrich.heiser@probiodrug.de, Department of Chemistry, probiodrug AG, Weinbergweg 22, Halle (Saale), 06120, Germany
Amyloid Precursor Protein (APP) derived amyloid peptide (Abeta) depositions in brains of Alzheimer's syndrome (AD) -patients preferentially consist of N-terminal modified pyroglutamyl (pGlu) Abeta in contrast to Abeta-compositions found in non-demented, aged people. We have discovered that such pGlu-containing Abpeptides are originated by N-terminal glutamate cyclization facilitated by human Glutaminyl Cyclase (hQC, EC 2.3.2.5). This N-terminal modification leads to an increase of hydrophobicity, stability and proteolytic resistance of the pGlu-Abspecies, resulting therefore in a enhanced tendency to form aggregates and fibrils. Moreover, recent data suggest that those truncated Abeta-species have an impact on learning and memory and can cause neuronal apoptosis. Hence, the qualification of hQC as a potential target for the treatment of AD has led to the development of enzyme inhibitors as new potential drugs for AD-treatment and is pioneered by Probiodrug AG, Germany. We present here the progress made during development of new inhibitors of hQC as well as results of animal experiments which demonstrate the efficacy of QC inhibition preventing the pGlu-Abformation in vivo and the consequences of such treatment for animal behavior.
 

General Oral Session
9:00 AM-12:20 PM, Thursday, August 21, 2008 Pennsylvania Convention Center -- 204 A&B, Oral

Division of Medicinal Chemistry

The 236th ACS National Meeting, Philadelphia, PA, August 17-21, 2008