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

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.

Figure 1

Evolution of peptide signaling and information transfer in metazoans. Red arrows indicate external and environmental sensory information transfer into the organism. Black arrows indicate internal information transfer among cells and tissues. Stages 4–6 indicate the separation of tissues between those that receive external sensory information (blue) and those that are associated with the internal homeostatic interactions of the organism (pink). In Stage 6, internal peripheral signals from internal organs and tissues are indicated in black, whereas, CNS outflow to the peripheral organs and tissues is indicated in green.

Figure 2

A possible scheme for the phylogenetic relationships among TCAP-, CRF-, Calcitonin-, and Secretin-associated peptide families. Arrows indicate peptide families found in extant organisms.