Potent Macrocyclic Inhibitory Peptide with anti-amyloid effect in Alzheimer’s animal model
Prof. Aphrodite Kapurniotu, Technische Universität München
Bayerische Patentallianz GmbH
Despite the documented evidence that most of the symptomatology of Alzheimer’s disease (AD) is attributed to the presence of oligomers of the β‐amyloid peptide (Aβ) peptides in the brain, several anti‐Aβ therapies blocking amyloid self-assembly have previously failed. Reasons for unsuccessful design and therapeutic application range from low proteolytic stability and blood–brain barrier (BBB) permeability as well as high conformational flexibility. However, amyloid peptides and their self-assembly remain the ideal target to combat AD. For this reason there is an urgent need to develop novel classes of amyloid inhibitors and exploit the therapeutic potential of blocking amyloidogenesis and related cell degeneration.
Macrocyclic inhibitory peptides (MCIPs) were designed as a new class of highly potent nanomolar inhibitors of amyloid plaque formation. Their drug-like properties including high solubility, cell permeability, binding affinity and target selectivity make them ideal drug candidates. Our lead candidate 2E is selective against Aβ40(42) as the main component of amyloid plaques.
In vivo data from a murine Alzheimer's model shows decreased oligomer levels and amyloid plaque load in the cerebral cortex. In addition, behaviorual tests demonstrate the candidate's effectiveness in partially restoring locomotive impariments and protecting from spatial learning and memory deterioration.
Our lead compound was confirmed as a potent small molecule inhibitor of amyloidogenesis in a mouse model of Alzheimer’s disease:
•MW < 2000 Da
• Inexpensive synthetic production by routine solid phase synthesis
• High binding affinity and solubility
• High stability in human blood
• Effective crossing of human blood brain barrier (in cell model)
• Promising data from behavioral tests with no in vivo toxicity
Proof of concept of lead compound in 5XFAD mouse model of Alzheimer’s disease.
Nationalization phases initiated in EP and US
Angew Chem Int Ed Engl. 2018 Jun 16. doi: 10.1002/anie.201802979.