Researchers at Probiodrug AG (Probiodrug), a developer of small molecule inhibitors for the treatment of inflammatory and neurodegenerative diseases, recently presented an update on its human glutaminyl cyclase inhibitor program for the treatment of Alzheimer’s disease (AD) at the 236th National Meeting of the American Chemical Society in Philadelphia, PA, USA.
At the conference, scientists presented their progress in developing new inhibitors of the human Glutam(in)yl Cyclase (QC) enzyme, including results of experiments demonstrating the efficacy of QC inhibition in AD animal models and improvements in learning and memory.
During the past years, compelling evidence has been generated that the enzyme Glutam(in)yl Cyclase (QC) plays a major role in Alzheimer’s disease and may therefore represent a promising target for a causative treatment of AD. The enzyme under certain conditions is catalyzing the formation of modified amyloid beta peptides in the brain. These variations are caused by a cyclization of the N-terminal glutamate residue of truncated A beta peptide, a reaction catalyzed by QC. As a result, the peptide carries a pyroglutamate (pGlu) residue and becomes uncharged, hydrophobic, and degradation resistant.
Research has also shown that these variations are very toxic, tend to aggregate, and can form seeds of Abeta peptide aggregates and deposits found in the brain of patients suffering from AD. While plaques of AD patients largely consist of pyroglutamated amyloid beta peptides, the plaques in the brain of non-demented elderly consist mainly of full-length amyloid beta. Moreover, the modified peptides are forming preferentially the core of plaques found in AD patients’ brains.
“Based on these findings, we believe that we have identified a causal mechanism explaining plaque formation as well as neurotoxicity and early neuron loss in the brain of AD patients,” said Professor Hans-Ulrich Demuth (pictured), Professor for Pharmabiotechnology at the Anhalt University of Applied Sciences and also co-founder of Probiodrug. “Consequently, we have started a broad Medicinal Chemistry program to develop small molecule inhibitors of QC as a potential new treatment for Alzheimer’s Disease. We could already demonstrate in mouse models of AD, that treatment with QC inhibitors not only reduced the pyroglutamated variety of the A beta peptides but also the plaques and led to cognitive improvement.”
Probiodrug News Release (08/14/08)
Abstract (The 236th American Chemical Society National Meeting; Philadelphia, PA, 204 A&B, Oral, 9:00AM-12:00PM (08/21/08))