Christian Reinhard Otto Bartling
Medicinal Chemistry Research
Jagtvej 162, 2100 København Ø
My PhD project focuses around the question whether it is possible to modulate the development and progression of Alzheimer’s disease (AD) by inhibiting disease relevant protein-protein interactions (PPIs) using peptide ligands.
PPIs are vital for cellular and biochemical processes and hence are promising drug targets. However, targeting PPIs is often challenging as the binding sites are typically shallow and devoid of obvious binding pockets. The Munc18-interacting (Mint) protein family, Mint1-3, are multidomain scaffolding proteins comprising a phosphotyrosine binding domain (PTB) and two PSD-95/discs large/zonula occludens 1 (PDZ) domains. The two members, Mint1 and Mint2, are primarily expressed in neurons and being assigned to key functions in synaptic vesicle exocytosis, protein transport and synapse formation. Furthermore, Mint1 and Mint2 are important for amyloid precursor protein (APP) processing through a direct interaction via the endoplasmatic sorting motif of APP with the PTB domain in Mint. Proteases process APP into the plaque forming Aβ peptide, which is the main component of the toxic amyloid plaques found in excess in brains of patients suffering from AD.
By mapping the interaction between APP and Mint2, we envisioned to design novel PPI inhibitors for the Mint2/APP-interaction. After determining the minimal binding peptide sequence of APP, this peptide was subjected to extensive mutational scans, allowing us to highlight structural properties in the APP sequence crucial for the interaction with Mint2. Based on this data, peptides characterized by significantly improved affinity and metabolic stability have been developed. In collaboration, lead compounds have recently been tested in neurons. Importantly, we were able to show that these conceptually new inhibitors are able to reduce the formation of the toxic Aβ peptide.
In perspective, we expect that these novel peptide inhibitors will be evaluated in relevant AD models in vivo.