Peptide-based therapeutics: engineering galanin for systemic anticonvulsant and anagesic activity

Anticonvulsant neuropeptides have the ability to suppress seizures and modulate pain pathways. One such neuropeptide, galanin, offers a potential first-in-class therapeutic for the treatment of epilepsy and/or pain. This dissertation describes the method for engineering galanin into systemically-active, metabolically stable peptidebased drug leads that maintain anticonvulsant and analgesic activities. The galanin receptors are found both in the central nervous system as well as in the peripheral nervous system. To generate systemically bioavailable galanin, lipidization and cationization motifs are added to the bioactive fragment of galanin: this modulates the peptides' blood-brain barrier permeability. There are three receptor subtypes of galanin (GalR1, GalR2, and GalR3), and subtype specific galanin analogs have been synthesized by modifying the N-terminus of the galanin fragment. One subtype specific analog maintains its binding affinity towards GalR2, while significantly losing affinity for GalR1, and displays anticonvulsant activity in vivo. Finally, novel galanin analogs with metabolically-resistant motifs incorporated into the peptide backbone are generated and are found to be orally-bioavailable analgesic compounds. This work provides proof-of concept towards developing peptide-based therapeutics for the treatment of epilepsy and pain.