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

Christopher R Apostol,Michael L Heien,Gabriella Molnar,Kelsey Bernard,Mitchell J Bartlett,Chenxi Liu,Helena W Morrison,Robin Polt,John M Streicher,Torsten Falk,Parthasaradhireddy Tanguturi,Lajos Szabò,J Bryce Ortiz,Lalitha Madhavan,Tabitha R F Green,Katherine R Giordano,Maha Saber,Rachel K Rowe,James Melvin

doi:10.3389/fddsv.2021.818003

Abstract

There is an unmet clinical need for curative therapies to treat neurodegenerative disorders. Most mainstay treatments currently on the market only alleviate specific symptoms and do not reverse disease progression. The Pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenous neuropeptide hormone, has been extensively studied as a potential regenerative therapeutic. PACAP is widely distributed in the central nervous system (CNS) and exerts its neuroprotective and neurotrophic effects via the related Class B GPCRs PAC1, VPAC1, and VPAC2, at which the hormone shows roughly equal activity. Vasoactive intestinal peptide (VIP) also activates these receptors, and this close analogue of PACAP has also shown to promote neuronal survival in various animal models of acute and progressive neurodegenerative diseases. However, PACAP’s poor pharmacokinetic profile (non-linear PK/PD), and more importantly its limited blood-brain barrier (BBB) permeability has hampered development of this peptide as a therapeutic. We have demonstrated that glycosylation of PACAP and related peptides promotes penetration of the BBB and improves PK properties while retaining efficacy and potency in the low nanomolar range at its target receptors. Furthermore, judicious structure-activity relationship (SAR) studies revealed key motifs that can be modulated to afford compounds with diverse selectivity profiles. Most importantly, we have demonstrated that select PACAP glycopeptide analogues (2LS80Mel and 2LS98Lac) exert potent neuroprotective effects and anti-inflammatory activity in animal models of traumatic brain injury and in a mild-toxin lesion model of Parkinson’s disease, highlighting glycosylation as a viable strategy for converting endogenous peptides into robust and efficacious drug candidates.

Highlights

Traumatic brain injury (TBI) and Parkinson’s disease (PD) are problematic neurological disorders due to a lack of curative therapies and the global burden on health care systems
Pituitary adenylate cyclase-activating polypeptide (PACAP) is considered a “difficult peptide sequence” due to its length and presence of two dipeptide motifs within its structure that are prone to aspartimide formation (Dölling et al, 1994; Lauer et al, 1995; Subirós-Funosas et al, 2011; Paradís-Bas et al, 2016; Samson et al, 2019)
We addressed these problems by utilizing several different coupling protocols for the PACAP derivatives (Figure 4)

Summary

Introduction

Traumatic brain injury (TBI) and Parkinson’s disease (PD) are problematic neurological disorders due to a lack of curative therapies and the global burden on health care systems. None of the available therapies slow, prevent, or reverse the progression of PD (Smith et al, 2012), which inevitably leads to impaired cognition, severe motor skill deficits, heightened neuroinflammation, and dysregulation of brain homeostasis (Mattson, 2000). Traumatic brain injury (TBI) is a debilitating neurological disorder that affects roughly 69 million people worldwide each year (Dewan et al, 2019). Common clinical characteristics of TBI include cognitive and motor skill deficits, confusion, temporary loss of consciousness, and coma in severe cases (Andriessen et al, 2010). Novel restorative and anti-inflammatory treatments for TBI are necessary

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Conclusion