Glutaminyl Cyclase (QC) is an enzyme responsible for pyroglutamate formation of beta amyloids peptides. Inhibition of QC activity can potentially act as an AD therapy or even prevention as plaque cores consist entirely of pyroglutamated beta amyloids

Inhibition of Glutaminyl Cyclase (QC) activity in beta amyloid plaques in AD.

Many compounds in development for Alzheimer's Disease (AD), are aimed at the plaques and tangles which have been identified as the major culprits of the disease. It has long been known that plaques are caused by accumulation of beta amyloid peptide, which is a cleavage product of amyloid precursor protein (APP). Much attention has been given to the C-terminus cleavage products i.e. beta-amyloids. Recently it has been found that there are cleavage products at the N-terminus end as well, and that a particular modification may be the major culprit in disease onset. Based on this finding, Probiodrug is working on AD from the N-terminus end. It is known that the majority of amyloid beta peptide deposited in the brains of AD patients is N-truncated. Moreover, varieties containing pyroglutamate at position three represent the predominant form among the N-truncated species and account for between 35% and 50% of the amyloid beta accumulated in plaques. The core of the plaques consists almost entirely of pyroglutamated beta amyloids. Studies of the various beta amyloid species have concluded that the morphology of the beta amyloid peptides is greatly influenced by the C-terminus, while toxicity, interaction with cell membranes and degradation are influenced by the N-terminus. Pyroglutamated species induced significantly more cell loss than the other species in cell cultures, and they aggregate preferentially within the cytoplasm of treated cells and on the plasma membrane. Moreover, they showed significant resistance to degradation. Pyroglutamate formation makes the beta amyloid resistant to cleavage by aminopeptidases, and as a result, the pyroglutamated species accumulate and act as a seeding factor, provoking plaque formation. Probiodrug has identified Glutaminyl Cyclase (QC) as the precursor enzyme responsible for pyroglutamate formation. QC is a metalloenzyme involved in peptide hormone final maturation. QC is known to catalyse pyroglutamate formation through glutamine cyclization, a common post-translational event during the biosynthesis of bioactive peptides. Probiodrug has been able to suppress the conversion of N-terminal glutamic acid to pyroglutamate via QC inhibition in vitro and in vivo. Indeed, long lasting or complete inhibition of QC activity might not even be necessary, as the catalytic activity of QC on beta amyloid is slow compared to normal beta amyloid degradation. A therapy or even prevention could consist of partial inhibition of QC activity and stimulators of degrading enzymes such as extracellular proteases. This combination would shift APP breakdown toward the normal breakdown mechanisms. Probiodrug hopes to take compounds into the clinic at the end of 2006 or early 2007.

Preclinical

WO 2004/098625 and WO 2005/039548, Use of effectors of glutaminyl and glutamate cylases. WO 2004/098591, Inhibitors of Glutaminyl Cyclase. WO 2005/049027, Combinations useful for the treatment of neuronal disorders. WO 2005/075436, Novel inhibitors of glutaminyl cyclase.

Probiodrug is looking for a pharma partner who is willing to enter into a: - A) A research collaboration, and B) A license agreement for our developmental compounds.