QC-Inhibitors
Glutaminyl cyclase (QC) is an enzyme catalyzing the formation of pyroglutamic peptides or proteins from an N-terminal glutamine residue.
While it was assumed for a long time that all QC enzymes show a strict specificity for glutamine in the N-terminal position of proteins, Probiodrug discovered that under certain conditions human QC can perform a second catalytic step: the conversion of a N-terminal glutamate to form so-called pyroglutamated (pGlu) peptide species (Glutamyl cyclase activity – EC).
As pGlu-formation leads to stabilization of a peptide and protection against cleavage this reaction plays an important role in several diseases.
Probiodrug is focusing on inflammation-related diseases, e. g. Alzheimer’s Disease (AD) and cardiovascular indications.
In cardiovascular diseases, QC is involved in inflammation by forming pGlu-residues of regulatory peptides such as monocyte chemotactic protein-1 (MCP-1). This protein recruits monocytes to sites of injury and infection. A pGlu-modification leads to prolonged systemic stability of MCP-1 and to a prolonged binding to receptors, which are crucial for enhancing inflammatory processes. Inhibiting pGlu-formation therefore is thought to diminish MCP-1’s inflammatory potential.
In Alzheimer’s disease (AD), pGlu-formation of amyloid beta (Aβ) peptides leads to peptide species with increased neurotoxicity, a prolonged half-life and an increased tendency for aggregation. Moreover, pyroglutamated peptides account for more than 50 % of the whole Aβ deposited in the typical plaques observed in the brain of AD patients.
In in vivo pharmacological studies, Probiodrug has shown that inhibition of QC leads to reduction of pyroglutamated Aβ and improvement of cognitive abilities.
Probiodrug therefore believes that inhibition of neuronal QC is the first causative approach in the treatment for Alzheimer’s disease.
AD is a significant indication: In 2007, about 29 million people worldwide were suffering from Alzheimer’s diseases and by 2050, the prevalence will quadruple, by which time 1 in 85 persons worldwide will be living with the disease.