Exploring Novel PACAP-Derived Glycopeptides: Synthesis, and Therapeutic Potential for Neuroprotection

Abstract

Neurodegenerative disorders such as Parkinson’s disease (PD) and traumatic brain injury (TBI) represent complex, multifactorial conditions for which current treatments primarily address symptoms rather than underlying causes. This dissertation first provides a comprehensive review of the therapeutic landscape of neurodegenerative disorders, therapeutic peptides, and the Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) system in chapters 1-3. It then investigates the therapeutic potential of glycosylated analogues of PACAP, an endogenous neuropeptide with known neuroprotective properties. Building on prior structure-activity relationship (SAR) insights, novel PACAP-derived glycopeptides, termed “truncamers”, were synthesized using optimized solid-phase peptide synthesis (SPPS) methods, including strategies to minimize aspartamide formation and monitor Fmoc deprotection via UV-Vis spectroscopy.These analogues utilize glycosylated amino acid building blocks, synthesized through minimally competent Lewis acid catalysis, to enhance blood-brain barrier permeability, enzymatic stability, and modified membrane interaction via amphipathic “Biousian” behavior. Structural and functional evaluations of circular dichroism (CD), plasmon waveguide resonance (PWR), and cAMP mobilization assays reveal that glycosylation induces Biousian properties while preserving PAC1 receptor activity. In vivo efficacy was further validated using a rodent model of TBI, where select “truncamers” significantly ameliorated motivational deficits linked to lateral habenula dysfunction. This work demonstrates the promise of PACAP glycopeptides as a platform for CNS-active drug development and contributes new synthetic tools and biological insights toward achieving truly neuroprotective therapeutics.