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

Christopher R Apostol; Parthasaradhireddy Tanguturi; Lajos Z Szabò; Daniel Varela; Thiago Gilmartin; John M Streicher; Robin Polt

doi:10.3390/molecules26164932

Synthesis and In Vitro Characterization of Glycopeptide Drug Candidates Related to PACAP_1-23

Molecules. 2021 Aug 14;26(16):4932. doi: 10.3390/molecules26164932.

Authors

Christopher R Apostol¹, Parthasaradhireddy Tanguturi², Lajos Z Szabò¹, Daniel Varela³, Thiago Gilmartin³, John M Streicher², Robin Polt¹

Affiliations

¹ Department of Chemistry and Biochemistry, BIO5, The University of Arizona, 1306 E. University Blvd, Tucson, AZ 85721, USA.
² Department of Pharmacology, College of Medicine, The University of Arizona, 1501 N. Campbell Ave, Tucson, AZ 85724, USA.
³ Facultat de Quìmica Tarragona, Universitat Rovera I Virgili, 43007 Barcelona, Spain.

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 PACAP_1-23 is capable of inducing neuroprotection in vitro, we were inspired to synthesize shortened glycopeptide analogues of PACAP_1-23. Herein, we report the synthesis and in vitro characterization of glycosylated PACAP_1-23 analogues that interact strongly with the PAC1 and VPAC1 receptors, while showing reduced activity at the VPAC2 receptor.

Keywords: Alzheimer’s; Parkinson’s; glycopeptide; glycosylation; stroke.

MeSH terms

Brain / drug effects
Brain / metabolism
Glycopeptides / chemical synthesis
Glycopeptides / chemistry*
Glycopeptides / pharmacology
Humans
Inflammation / drug therapy*
Inflammation / pathology
Neurodegenerative Diseases / drug therapy*
Neurodegenerative Diseases / pathology
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / chemistry
Neuroprotective Agents / pharmacology
Peptide Fragments / chemical synthesis
Peptide Fragments / chemistry*
Peptide Fragments / pharmacology
Peptide Hormones / chemical synthesis
Peptide Hormones / chemistry
Peptide Hormones / pharmacology
Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / drug effects
Receptors, Vasoactive Intestinal Peptide, Type II / antagonists & inhibitors
Receptors, Vasoactive Intestinal Polypeptide, Type I / drug effects

Substances

Glycopeptides
Neuroprotective Agents
Peptide Fragments
Peptide Hormones
Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
Receptors, Vasoactive Intestinal Peptide, Type II
Receptors, Vasoactive Intestinal Polypeptide, Type I

Grants and funding

R01NS091238/NS/NINDS NIH HHS/United States