Selective PYY Peptides for Y2 Receptor Agonism
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Solution Overview
Problem
Current PYY(3-36) analogues have suboptimal pharmacokinetic properties, requiring frequent administration due to rapid elimination, and lack specificity for the Y2 receptor subtype, which is desirable for treating obesity and diabetes.
Innovation Solution
Development of PYY compounds with specific modifications, including lysine at position 7 or 10, tryptophan at position 30, leucine at position 31, tyrosine at position 28, and isoleucine at position 22, along with a modifying group attached to the epsilon amino group of lysine, to enhance Y2 receptor selectivity and prolong half-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If PYY(3-36) is used for treatment, then Y2 receptor agonist activity is achieved, but half-life is short and clearance is rapid
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of PYY(3-36) through specific substitutions (e.g., position 7, 10, 30, 31, 28, 22) to alter pharmacokinetic parameters. These modifications increase half-life and decrease clearance while preserving Y2 receptor agonist activity, directly resolving the contradiction between duration of action and pharmacokinetic reliability.
Solution Approach 2:
The patent creates composite peptide structures by combining multiple amino acid modifications within the PYY framework. The synergistic effect of several specific amino acid changes produces a compound with improved pharmacokinetic properties that neither single modification could achieve alone, addressing the half-life and clearance issues simultaneously.
2Reliability
If PYY analogues are used for treatment, then Y2 receptor agonist activity is achieved, but specificity for Y2 receptor subtype is insufficient
Solution Approach 1:
The patent applies local quality by making specific amino acid modifications at particular positions (7, 10, 30, 31, 28, 22) within the PYY molecule. Each modification is strategically placed to enhance Y2 receptor selectivity without requiring comprehensive changes throughout the entire peptide structure, thus achieving high specificity with targeted rather than universal modifications.
Solution Approach 2:
The patent uses parameter changes by systematically varying amino acid residues at specific positions to optimize Y2 receptor binding selectivity. Through controlled changes in amino acid composition and sequence, the patent achieves high Y2 subtype specificity while maintaining manageable structural complexity.
3Ease of operation
If PYY or PYY(3-36) is administered, then therapeutic effect is achieved, but dosing frequency must be high
Solution Approach 1:
The patent resolves this contradiction by changing pharmacokinetic parameters through amino acid modifications. The modified compounds exhibit extended half-life and reduced clearance rates, which directly enable less frequent dosing while maintaining therapeutic efficacy, thus improving ease of operation without sacrificing duration of action.
Data Source
AI summary
The invention relates to PYY compounds with the amino acid modifications 7Lys, 30Trp, and 31Leu, and in addition to these, 22Ile and/or 28Tyr, and derivatives thereof. The compounds of the invention are selective Y2 receptor agonists. The invention also relates to pharmaceutical compositions comprising such PYY compounds and pharmaceutically acceptable excipients, as well as the medical use of the PYY compounds.