N-methylated Cyclic Hexapeptides for Oral Bioavailability
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Solution Overview
Problem
Current peptide-based cancer therapies face challenges such as low metabolic stability, poor absorption after oral ingestion, rapid excretion, and limited bioavailability due to high molecular mass and lack of specific transport systems, restricting their effectiveness and applicability.
Innovation Solution
Development of N-methylated cyclic hexapeptides with a head-to-tail cyclization and specific amino acid sequences like Arg, Gly, and Asp, which are formulated as prodrugs to enhance metabolic stability and oral bioavailability by masking charged groups and improving intestinal permeability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If peptide-based cancer therapies are administered orally, then they can be delivered systemically, but they exhibit poor absorption and low bioavailability due to high molecular mass and lack of specific transport systems
Solution Approach 1:
The peptide is cyclized to form a cyclic hexapeptide structure, which segments the linear chain into a closed ring configuration. This structural segmentation reduces molecular flexibility and enhances stability against proteolytic degradation, thereby improving oral bioavailability while maintaining the ability to bind to integrin αvβ3
Solution Approach 2:
The peptide incorporates N-methylated amino acid residues combined with specific amino acid sequences (Arg, Gly, Asp) to create a composite structure. The N-methylation modifies the peptide's physical and chemical properties, enhancing membrane permeability and oral absorption while the specific sequence maintains high affinity for integrin αvβ3
2Reliability
If peptide-based cancer therapies are used, then they can target integrins in tumor progression, but they exhibit low metabolic stability and rapid excretion
Solution Approach 1:
The peptide is pre-modified with N-methyl groups on specific amino acid residues before administration. This preliminary chemical modification protects the peptide from enzymatic degradation by proteases, extending its metabolic stability and duration of action in the bloodstream while preserving its ability to target integrins
Solution Approach 2:
The peptide incorporates D-amino acid residues in specific positions alongside L-amino acids. This partial use of D-amino acids provides resistance to proteolytic degradation at those specific sites without completely altering the peptide's overall structure or binding capability to integrin αvβ3
3Reliability
If N-methylated cyclic hexapeptides are developed with high affinity to integrin αvβ3, then they achieve high selectivity, but they may lose oral availability due to increased polarity
Solution Approach 1:
N-methylation is applied selectively to specific amino acid residues at defined positions within the cyclic hexapeptide structure, rather than uniformly to all residues. This localized modification enhances oral availability at specific sites while maintaining the critical Arg-Gly-Asp sequence integrity for high selectivity binding to integrin αvβ3
Data Source
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Figure 3A~3B
AI summary
The present invention provides N-methylated cyclic hexapeptides comprising RGD and at least one alanine residue. The present invention further provides prodrugs comprising the cyclic hexapeptides. Pharmaceutical compositions comprising said cyclic hexapeptides are also disclosed as well as methods of their production and use in treating integrin related conditions and diseases.