Macrocyclic Peptides for ER Stress Disease Treatment
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Solution Overview
Problem
Natural unmodified CDNF and MANF peptides are poor drug molecules due to quick metabolism and poor distribution when administered, limiting their use as pharmaceutical products for treating degenerative and chronic diseases associated with ER stress.
Innovation Solution
Development of novel stabilized macrocyclic peptides derived from the C-terminal domain of CDNF and MANF, specifically 8-32 amino acid peptides in a macrocyclic form, which improve metabolic stability and distribution properties without losing cell-protective activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If natural unmodified CDNF and MANF peptides are used, then cell-protective activity is achieved, but metabolic stability and distribution properties deteriorate
Solution Approach 1:
The patent applies parameter changes by modifying the peptide structure through macrocyclization and incorporating non-natural amino acids. This transforms the linear natural peptides into cyclic structures with altered pharmacokinetic properties, specifically improving metabolic stability while preserving the bioactive C-terminal domain that provides cell-protective activity
Solution Approach 2:
The patent creates composite peptide structures by combining natural amino acid sequences with non-natural amino acid residues. This composite approach allows the peptide to maintain its biological function while gaining enhanced stability and resistance to degradation, effectively merging the benefits of natural and synthetic components
2Reliability
If natural unmodified CDNF and MANF peptides are used, then cell-protective activity is achieved, but distribution properties deteriorate
Solution Approach 1:
The patent modifies distribution properties through parameter changes in the peptide structure, specifically by macrocyclization and adding lipid-like moieties. These structural changes alter the peptide's pharmacokinetic profile, improving tissue penetration and distribution without compromising the cell-protective function of the C-terminal domain
3Stability of the object's composition
If peptide length is reduced to 8-32 amino acids, then metabolic stability improves, but structural complexity must be optimized
Solution Approach 1:
The patent applies segmentation by dividing the full-length CDNF/MANF protein into a focused C-terminal domain fragment (8-32 amino acids). This segmentation isolates the essential bioactive region while removing unnecessary portions, thereby improving metabolic stability and simplifying the structure to only the critical functional elements
4Stability of the object's composition
If macrocyclic form is adopted, then metabolic stability and distribution properties improve, but manufacturing complexity increases
Solution Approach 1:
The patent addresses manufacturing complexity through parameter changes in the synthesis approach, using solid-phase peptide synthesis with pre-formed cyclic constraints or native chemical ligation methods. These optimized synthesis parameters enable efficient production of the macrocyclic structure while maintaining the desired metabolic stability and distribution properties
Data Source
AI summary
The present disclosure relates to the field of unconventional neurotrophic factors and to the field of treating degenerative, chronic or progressive diseases and disorders, and monogenic hereditary diseases having ER stress as a pathogenic compound. More particularly the disclosure relates to modified peptides, particularly macrocyclic peptides. The disclosure also relates to pharmaceutical compositions comprising said peptides. Further, the disclosure also relates to said peptides, and pharmaceutical compositions for use as a medicament and in the treatment of degenerative, chronic or progressive diseases and disorders, and monogenic hereditary diseases having ER stress as a pathogenic compound as well as to methods for treating said diseases and disorders.