Rational Design of Peptidomimetics Targeting Glucagon-Like Peptide-1 Receptors

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Protein complex formation through protein-protein or receptor-ligand interaction is a central theme in biological systems and plays critical roles in regulating diverse cellular functions. It is often mediated by α-helical structures and this recognizes short helical peptides as valuable tools to study critical biochemical pathways as well as to ultimately develop therapeutic candidates. However, peptides have serious limitations, such as rapid enzymatic degradation, low bioavailability, and no oral activity, that potentially hamper their effective applications. Thus, non-peptidic α-helix mimetics would be of great interest due to their potentially high enzymatic stability and efficacy. However, α-helix mimetics already reported until now do not represent amphiphilicity, a fundamental feature of most α-helices that significantly contributes to potency and selectivity. Therefore, I have developed a research plan that focuses on development of amphiphilic α-helix mimetics and their applications to emulate α-helical structures found in peptides and proteins. Simultaneous representation of both hydrophobic and hydrophilic surfaces will be important to achieve not only high affinity but also improved selectivity for their target proteins. To demonstrate proof of concepts, we have chosen a peptide hormone, glucagon like peptide-1 (GLP-1) that plays an important physiological role in glucose homeostasis through stimulating insulin secretion and regulating pancreatic β-cell mass and functions, which are highly favorable for treating diabetes. However, its high susceptibility to enzymatic degradation becomes a major obstacle for its effective in vivo applications and highlights the need of potent non-peptide GLP-1 mimetics that have not been achieved yet. Thus, we herein propose a rational approach to design GLP-1 peptidomimetics containing α-helix mimetics that are engineered to represent corresponding α-helical peptide segments in GLP-1. As a seminal observation, one of our recently synthesized prototype α-helix mimetics was found to interact with the GLP-1 receptor and induce receptor stimulation. Furthermore, this compound showed markedly enhanced biological activity when linked to a complementary GLP-1 fragment and led to develop potent GLP-1 peptidomimetics. Encouraged by our initial success, in this research plan we propose (1) to identify important helical faces for receptor interaction by using α-helix mimetics based on the tris-benzamide scaffold; (2) to design and synthesize amphiphilic α-helix mimetics to improve α-helix mimicry for higher potency and selectivity to the GLP-1 receptor; (3) to rationally design and construct GLP-1 peptidomimetics using the α-helix mimetics; (4) to improve biological activity of GLP-1 peptidomimetics through a multivalent architecture; and (5) to characterize and validate α-helix mimicry by structural analysis. The strategies developed in this proposal would be of interest since they can be broadly applied to other medically relevant targets.