PYY Analogue Composition for Solubility and Extended Half-Life
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current PYY analogues have a short half-life and undesirable chemical properties, limiting their efficacy as body weight lowering agents, and there is a need for PYY analogues that are selectively acting on the NPY2 receptor with improved solubility and stability.
Innovation Solution
Development of PYY analogues with specific amino acid modifications and attachment of a half-life extending group to the epsilon amino group of lysine or carboxylic acid group of aspartate/glutamate, enhancing solubility around pH 6 and pH 7, and potentially combining with other therapeutics for improved efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PYY analogues are used as body weight lowering agents, then they can suppress food intake via NPY2 receptor activation, but they have short half-life and low stability limiting their efficacy
Solution Approach 1:
The patent extracts the active pharmacophore (PYY (3-36) sequence) from the full PYY molecule and combines it with a separate half-life extending group (albumin-binding moiety). This separation allows the active peptide to maintain its receptor-binding capability while the attached albumin-binding group provides prolonged circulation time by preventing renal clearance and proteolytic degradation.
Solution Approach 2:
The patent creates a composite molecule combining two distinct functional components: the PYY (3-36) peptide sequence for NPY2 receptor activation and an albumin-binding moiety for extended half-life. This composite structure integrates the pharmacological activity of PYY with the long circulation properties of albumin, achieving both efficacy and prolonged duration of action.
2Reliability
If PYY analogues are used as body weight lowering agents, then they can suppress food intake via NPY2 receptor activation, but they show undesirable chemical properties including low stability
Solution Approach 1:
The patent extracts the essential pharmacophore (PYY (3-36) sequence) from the full PYY molecule and combines it with a separate half-life extending group (albumin-binding moiety). This separation allows the active peptide to maintain its receptor-binding capability while the attached albumin-binding group provides prolonged circulation time by preventing renal clearance and proteolytic degradation.
Solution Approach 2:
The patent creates a composite molecule combining two distinct functional components: the PYY (3-36) peptide sequence for NPY2 receptor activation and an albumin-binding moiety for extended half-life. This composite structure integrates the pharmacological activity of PYY with the long circulation properties of albumin, achieving both efficacy and prolonged duration of action.
3Duration of action of stationary object
If PYY analogues are developed with half-life extending groups, then duration of action is improved, but solubility around pH 6-7 needs to be increased for formulation options
Solution Approach 1:
The patent systematically varies the amino acid sequence parameters of the PYY analogue, specifically at positions 4, 9, and 30, to optimize both solubility and half-life properties. By changing the chemical nature of residues at these positions (e.g., introducing charged or polar amino acids), the patent achieves improved solubility at physiological pH while maintaining the albumin-binding capability for extended half-life.
Data Source
AI summary
The invention relates to PYY analogues having alanine at position 4, lysine at position 7, QRY as the C-terminal end and a half-life extending group. The analogues of the invention are soluble around pH 6 and 7. The invention also relates to pharmaceutical compositions comprising such PYY analogues, and to the medical use of the analogues.