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Front Endocrinol (Lausanne). 2019 Nov 12;10:730. doi: 10.3389/fendo.2019.00730. eCollection 2019.

Synthetic Peptides as Therapeutic Agents: Lessons Learned From Evolutionary Ancient Peptides and Their Transit Across Blood-Brain Barriers.

Author information

1
Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada.
2
Protagenic Therapeutics Inc., New York, NY, United States.
3
Department of Pediatrics, University of Alabama, Birmingham, AL, United States.
4
Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada.

Abstract

Peptides play a major role in the transmission of information to and from the central nervous system. However, because of their structural complexity, the development of pharmacological peptide-based therapeutics has been challenged by the lack of understanding of endogenous peptide evolution. The teneurin C-terminal associated peptides (TCAP) possess many of the required attributes of a practical peptide therapeutic. TCAPs, associated with the teneurin transmembrane proteins that bind to the latrophilins, members of the Adhesion family of G-protein-coupled receptors (GPCR). Together, this ligand-receptor unit plays an integral role in synaptogenesis, neurological development, and maintenance, and is present in most metazoans. TCAP has structural similarity to corticotropin-releasing factor (CRF), and related peptides, such as calcitonin and the secretin-based peptides and inhibits the (CRF)-associated stress response. Latrophilins are structurally related to the secretin family of GPCRs. TCAP is a soluble peptide that crosses the blood-brain barrier and regulates glucose transport into the brain. We posit that TCAP represents a phylogenetically older peptide system that evolved before the origin of the CRF-calcitonin-secretin clade of peptides and plays a fundamental role in the regulation of cell-to-cell energy homeostasis. Moreover, it may act as a phylogenetically older peptide system that evolved as a natural antagonist to the CRF-mediated stress response. Thus, TCAP's actions on the CNS may provide new insights into the development of peptide therapeutics for the treatment of CNS disorders.

KEYWORDS:

CRF; G-protein coupled receptors; blood-brain barrier; latrophilin; neuroplasticity; receptor-ligand interaction; secretin; stress

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