Cyclic Peptides Targeting CD44v6 for Cancer Metastasis
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Solution Overview
Problem
Current treatments for cancers such as pancreatic and liver cancer, particularly after metastasis has occurred, are ineffective in providing long-term progression-free survival or regression of metastases, and there is a need for new compounds that can inhibit metastasis and angiogenesis to prevent tumor growth.
Innovation Solution
Development of cyclic peptides with specific amino acid sequences, including R-W-H, and featuring chemical bonds between amino acid side chains, which are resistant to proteolytic degradation and exhibit enhanced pharmacological activity by interacting effectively with receptors, thereby blocking cMET and Erk activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional chemotherapy (gemcitabine, oxaliplatin, cisplatin) is used to treat pancreatic cancer, then some tumor growth inhibition is achieved, but long-term progression-free survival is not provided and metastases cannot be effectively regressed
Solution Approach 1:
The invention changes the chemical structure parameters of the treatment agent by using cyclic peptides with specific amino acid sequences (X1-X2-X3-R-W-H-X11) and non-peptide bonds instead of conventional chemotherapy agents like gemcitabine. This structural parameter change enables the peptide to specifically block CD44v6-mediated activation of receptor-tyrosine-kinases, providing reliable long-term progression-free survival while maintaining treatment effectiveness.
Solution Approach 2:
The invention creates a composite therapeutic approach by combining cyclic peptide structure (with non-peptide bonds for stability) and specific amino acid sequences (including R-W-H motif) that target multiple pathways (CD44v6, cMET, VEGFR). This composite design provides both reliable disease control and effective metastasis regression, overcoming the limitations of single-agent conventional chemotherapy.
2Reliability
If peptides are designed to block CD44v6 mediated activation of receptor-tyrosine-kinases, then pharmacological activity is enhanced, but the peptides are susceptible to proteolytic degradation
Solution Approach 1:
The invention changes the chemical bond parameters within the peptide structure by incorporating non-peptide bonds (such as amide bonds, ester bonds, or other stable linkages) between amino acid residues. This parameter change maintains the peptide's ability to block CD44v6-mediated activation of receptor-tyrosine-kinases while simultaneously protecting it from proteolytic degradation, thereby achieving both high pharmacological activity and stability.
Solution Approach 2:
The invention creates a composite peptide structure combining amino acid residues (with specific sequences including R-W-H motif) and non-peptide bonds. This composite structure provides both the biological activity needed to block CD44v6-cMET-VEGFR signaling pathways and the chemical stability required to resist proteolytic enzymes in the tumor microenvironment, achieving enhanced pharmacological effectiveness.
3Ease of manufacture
If standard peptide bonds are used in cyclic peptides, then the structure is simple to form, but the peptides are rapidly degraded by proteases in the body
Solution Approach 1:
The invention changes the bond type parameter within the cyclic peptide by replacing one or more standard peptide bonds with non-peptide bonds (such as amide bonds, ester bonds, disulfide bridges, or other stable linkages). This parameter change maintains the ease of cyclic structure formation while dramatically increasing resistance to proteolytic degradation, thereby extending the peptide half-life in the body and duration of anti-angiogenic and anti-metastatic action.
Data Source
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Figure 3A~3B
AI summary
The present invention relates to compounds, pharmaceutical compositions and methods for treating different forms of cancer and angiogenesis related diseases using cyclic peptides.