Synthesis and In Vitro Characterization of Glycopeptide Drug Candidates Related to PACAP1–23

Abstract

The search for efficacious treatment of neurodegenerative and progressive neuroinflammatory diseases continues, as current therapies are unable to halt or reverse disease progression. PACAP represents one potential therapeutic that provides neuroprotection effects on neurons, and also modulates inflammatory responses and circulation within the brain. However, PACAP is a relatively long peptide hormone that is not trivial to synthesize. Based on previous observations that the shortened isoform PACAP1–23 is capable of inducing neuroprotection in vitro, we were inspired to synthesize shortened glycopeptide analogues of PACAP1–23. Herein, we report the synthesis and in vitro characterization of glycosylated PACAP1–23 analogues that interact strongly with the PAC1 and VPAC1 receptors, while showing reduced activity at the VPAC2 receptor.

Design and Synthesis of Brain Penetrant Glycopeptide Analogues of PACAP With Neuroprotective Potential for Traumatic Brain Injury and Parkinsonism

“…One possibility in the future would be to evaluate a recent series of shorter PACAP glycopeptide analogues that showed varying receptor profiles between PAC1, VPAC1 and VPAC2 ( Apostol et al, 2021 ). Notably, the two compounds were administered i.p.…”

“…The cell lines, culture, and cAMP assay are all described in our previous work ( Apostol et al, 2021 ). Briefly, human PAC1, VPAC1, and VPAC2 receptors expressed in CHO cells were used for all experiments.…”