Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC₂ Agonism and Glucose-Dependent Insulin Secretion

Abstract

Agonists of vasoactive intestinal peptide receptor 2 (VPAC 2 ) stimulate glucose-dependent insulin secretion, making them attractive candidates for the treatment of hyperglycaemia and type-II diabetes. Vasoactive intestinal peptide (VIP) is an endogenous peptide hormone that potently agonizes VPAC 2 . However, VIP has a short serum half-life and poor pharmacokinetics in vivo and is susceptible to proteolytic degradation, making its development as a therapeutic agent challenging. Here, we investigated two peptide cyclization strategies, lactamisation and olefin-metathesis stapling, and their effects on VPAC 2 agonism, peptide secondary structure, protease stability, and cell membrane permeability. VIP analogues showing significantly enhanced VPAC 2 agonist potency, glucose-dependent insulin secretion activity, and increased helical content were discovered; however, neither cyclization strategy appeared to effect proteolytic stability or cell permeability of the resulting peptides.

Getting Across the Cell Membrane: An Overview for Small Molecules, Peptides, and Proteins

“…Macrocyclic drugs—those with a ring architecture of 12 or more atoms, including cyclic peptides—tend to be larger and more polar than most small-molecule drugs, falling outside the Rule of 5 [120, 121]. Yet some are administered orally [121], suggesting that they may be membrane permeable [43, 99, 122].…”

Stapled peptide design: principles and roles of computation

“…For example, both single hydrocarbon and lactam staples were shown to be ineffective in enhancing the protease resistance of the 30-residue vasoactive intestinal peptide [67]. Multiple staples might then be required to protect the entire length of the peptide from proteolytic degradation.…”

Protease-Resistant and Cell-Permeable Double-Stapled Peptides Targeting the Rab8a GTPase

“…[37][38][39] Even though stapled peptides show improved cellular uptake and proteolytic stability, these improvements are in many cases not sufficient to ensure adequate bioactivity. 26,36,[40][41][42] The incorporation of alternative modifications intended to convey more drug-like properties is often associated with a considerable loss of target 4 affinity. 29,30 Taken together, a general strategy for the installation of robust cellular uptake and protease resistance while maintaining high target affinity of the cyclic peptide is still lacking.…”