hAM15-52 Analogues for Amylin Receptor Potency and Stability
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Solution Overview
Problem
Current amylin analogues face challenges such as high fibrillation tendency, short in vivo half-life, and chemical instability at pH 7, limiting their effectiveness in treating obesity and diabetes.
Innovation Solution
Development of hAM15-52 analogues with specific amino acid substitutions at positions X11, X4, X37, and X38, enhancing amylin receptor potency while reducing adrenomedullin receptor potency, thereby improving stability and efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If native amylin (hAMY1-37) is used to achieve high amylin receptor potency, then the therapeutic effect for diabetes and obesity is improved, but the peptide exhibits high fibrillation tendency and short in vivo half-life
Solution Approach 1:
The patent applies parameter changes by systematically substituting amino acids at specific positions (X4, X11, X37, X38) in the hAM15-52 sequence to optimize the balance between amylin receptor potency and stability. The substitution of Lysine at position X11 with Arginine, Tryptophan, or Citrulline, along with modifications at positions X4, X37, and X38, creates analogues that maintain high AMY3R potency while reducing fibrillation tendency and improving chemical stability at physiological pH
Solution Approach 2:
The patent creates composite peptide structures by combining the hAM15-52 backbone (residues 15-52 of human adrenomedullin) with selective amino acid substitutions from amylin and other sources. This composite approach integrates the stability characteristics of adrenomedullin-derived sequences with the receptor-binding properties of amylin, resulting in hybrid peptides that exhibit improved pharmacological properties compared to native amylin
2Stability of the object's composition
If amino acid substitutions are made to reduce fibrillation tendency, then the stability is improved, but the amylin receptor potency may be reduced
Solution Approach 1:
The patent applies local quality by making targeted amino acid substitutions at specific positions (X4, X11, X37, X38) rather than throughout the entire sequence. The disulfide bridge between Cys2 and Cys7 is preserved to maintain structural integrity, while local modifications at the identified positions selectively reduce fibrillation tendency without compromising the receptor-binding epitope. This localized approach allows optimization of stability while preserving potency
3Duration of action of moving object
If amino acid substitutions are made to extend in vivo half-life, then the duration of action is improved, but the molecular structure becomes more complex
Solution Approach 1:
The patent extends in vivo half-life through parameter changes in the peptide sequence by substituting amino acids at positions known to affect metabolic stability. The substitutions at X4, X11, X37, and X38 modify the peptide's resistance to proteolytic degradation while maintaining a relatively simple overall structure based on the hAM15-52 framework, thus achieving longer duration of action without excessive structural complexity
Data Source
AI summary
The present invention relates to hAM15-52 analogues with improved amylin receptor (hAMY3R) potency (hAMY3R-EC50≤250 pM) and which are largely based on the sequence of the human adrenomedullin fragment hAM15-52. The invention further relates to hAM15-52 analogues that are selective amylin receptor (hAMY3R) agonists (hAMY3R-EC50≤250 pM and an hAM1R-EC50≥25 nM) and which are largely based on the sequence of the human adrenomedullin fragment hAM15-52. The hAM15-52 analogues according to the invention maintain the good physical stability of hAM15-52. The invention further relates to pharmaceutical compositions comprising such polypeptides and their use in the treatment of a medical condition such as obesity, NASH and/or diabetes.