Biologically Active Truncated Glycopeptides Derived from Pituitary Adenylate Cyclase Activating Polypeptide

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is a neuroactive peptide with therapeutic potential across neurological, metabolic, and inflammatory disorders, yet clinical translation is hindered by its poor stability and limited bioavailability. This study reports the design, synthesis, and characterization of C-terminally glycosylated PACAP “truncamers” aimed at improving pharmacokinetic properties while preserving receptor engagement. Solid-phase peptide synthesis was optimized using UV-Vis Fmoc removal profiling to identify synthetic bottlenecks and inform future routes. Biophysical analyses using Plasmon Waveguide Resonance demonstrated membrane binding and nanomolar-to-picomolar affinity for PAC1, VPAC1, and VPAC2 receptors. Glycosylation improved solubility and modulated receptor selectivity, particularly reducing VPAC2 activation. These findings establish PACAP glycopeptides as promising scaffolds for next-generation therapeutics with enhanced brain permeability and tunable bioactivity, offering a model for broader glycopeptide drug development.