Monomeric Peptide Multi-Agonists for Weight Loss and Glycemic Control
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Solution Overview
Problem
Current treatments for type 2 diabetes mellitus (T2DM) and obesity often induce nausea and vomiting, and fail to provide meaningful long-term weight loss while protecting β-islet cell mass.
Innovation Solution
Development of chimeric peptides that simultaneously activate the anorectic neuropeptide Y2-receptor (Y2-R), islet-protecting neuropeptide Y1-receptor (Y1-R), and glucoregulatory receptor Glucagon-Like Peptide-1 receptor (GLP1-R) to achieve significant weight loss and improved glucose tolerance without nausea.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If GLP-1 receptor agonists are used to stimulate glucose-dependent insulin secretion and suppress appetite, then glycemic control and hypophagic effects are improved, but nausea and vomiting occur in 20-50% of patients
Solution Approach 1:
The patent combines GLP-1 receptor agonist activity with PYY3-36 peptide sequence to create a chimeric peptide that activates both GLP-1 and Y2 receptors. This merging of functionalities allows the single agent to provide glycemic control through GLP-1 receptor activation while the PYY3-36 component targets Y2 receptors in the brain to suppress appetite without triggering the nausea and vomiting associated with GLP-1 receptor agonists alone.
Solution Approach 2:
The chimeric peptide serves multiple functions simultaneously: it acts as a GLP-1 receptor agonist for glycemic control, a PYY3-36 analog for appetite suppression, and a Y2 receptor agonist for central anorectic effects. This multi-functionality in a single molecule addresses both glycemic control and weight management while avoiding the gastrointestinal side effects of conventional GLP-1RAs.
2Productivity
If higher doses of GLP-1RAs are administered to enhance hypophagic response, then appetite suppression is improved, but dose tolerance is reduced in 15% of patients
Solution Approach 1:
The chimeric peptide merges GLP-1 receptor agonism with PYY3-36-based Y2 receptor agonism to achieve enhanced appetite suppression through dual receptor activation. This combination allows for effective hypophagic response at lower doses compared to GLP-1RAs alone, improving dose tolerance while maintaining or enhancing the hypophagic effect through synergistic action on both GLP-1 and Y2 receptors.
3Reliability
If conventional treatments are used for T2DM and obesity, then glycemic control is achieved, but meaningful long-term weight loss is not achieved
Solution Approach 1:
The chimeric peptide combines the glycemic control benefits of GLP-1 receptor agonism with the potent appetite suppression and weight loss effects of PYY3-36/Y2 receptor activation. This merging enables simultaneous achievement of glycemic control and meaningful long-term weight loss, addressing both T2DM management and obesity treatment in a single therapeutic agent.
Solution Approach 2:
The single chimeric peptide molecule provides universal therapeutic benefits for both glycemic control and weight management by activating multiple receptors (GLP-1 and Y2) with different functional outcomes. This multi-functionality allows one agent to address both glycemic control and sustained weight loss, which conventional single-target therapies fail to achieve simultaneously.
4Device complexity
If single-receptor targeting approaches are used, then mechanism of action is simple, but profound weight loss and β-cell protection cannot be achieved
Solution Approach 1:
The chimeric peptide merges GLP-1 receptor targeting with PYY3-36-based Y2 and Y1 receptor targeting into a single molecular structure. This merging creates a multi-receptor targeting mechanism that achieves profound weight loss through combined central anorectic effects (Y2) and islet protection (Y1), while maintaining relatively simple administration as a single subcutaneous injection.
Data Source
AI summary
A series of chimeric peptides that provide a mechanism for obesity treatment concomitant with T2DM in the form of dual agonism of the anorectic neuropeptide Y-receptor (Y2-R) and the glucoregulatory receptor GLP1-R. Preliminary results show that, dependent on the selected peptide, once-daily administration suppress FI in male and female rats can be reduced to 12-65% compared to baseline conditions before treatment, dependent on dose and age of animals, and glucose tolerance can be improved as well. Peptides also demonstrated Y1-receptor agonism, conferring protection on beta-islet cells against inflammatory damage. The peptides were designed by targeting serial anorectic pathways simultaneously and are promising candidates for modulating FI and glucoregulation in an efficacious and safe way.