Cyclic CAIX-Binding Peptides for Selective Radionuclide Tumor Uptake
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Solution Overview
Problem
Existing compounds targeting Carbonic Anhydrase IX (CAIX) for cancer diagnosis and therapy suffer from lack of selectivity, low tumor-to-background ratio, and stability issues, leading to ineffective imaging and therapeutic outcomes.
Innovation Solution
Development of cyclic peptides with specific modifications and effector groups, such as chelators, to enhance binding affinity, stability, and target selectivity for CAIX, allowing effective delivery of radionuclides to cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing compounds targeting CAIX are used for cancer diagnosis and therapy, then they can potentially bind to CAIX, but they suffer from lack of selectivity, low tumor-to-background ratio, and stability issues
Solution Approach 1:
The patent modifies the peptide structure by introducing specific amino acid substitutions (e.g., Xaa1 as aliphatic or polar L-α-amino acid, Xaa2 as N-methylated L-α-amino acid, Xaa3 as L-α-amino acid with functional group FG1) and cyclic constraints to optimize binding affinity and selectivity while maintaining stability. These parameter changes in molecular structure directly address the contradiction between reliability and stability.
Solution Approach 2:
The invention creates composite structures by combining peptide sequences with effector groups (such as chelators) and modifying amino acid residues with specific functional groups. This composite approach enhances both binding reliability and molecular stability simultaneously.
2Productivity
If existing CAIX-targeting compounds are used, then they can potentially deliver radionuclides to cancer cells, but they result in low tumor uptake and high off-target effects
Solution Approach 1:
The patent introduces specific local modifications at key positions in the peptide sequence (Xaa1, Xaa2, Xaa3, Xaa6, Xaa11) with specific functional groups to enhance local binding interactions with CAIX. This localized optimization improves tumor uptake efficiency while minimizing off-target effects through increased selectivity.
Solution Approach 2:
The effector groups (such as chelators) serve as intermediaries that facilitate specific binding to CAIX while enabling radionuclide delivery. These intermediary structures mediate between the peptide and the target, improving delivery efficiency and reducing off-target effects.
3Ease of manufacture
If simple peptide structures are used, then they are easier to manufacture, but they lack sufficient binding affinity (pEC50 ≥ 6.0) and selectivity for CAIX
Solution Approach 1:
The patent segments the peptide structure into distinct functional regions with specific amino acid positions (Xaa1-Xaa12) that can be independently optimized. This segmentation allows for systematic improvement of binding affinity while maintaining a relatively simple overall structure that remains manufacturable.
Solution Approach 2:
The invention makes targeted parameter changes at specific positions (introducing N-methylated amino acids, amino acids with specific functional groups, cyclic constraints) rather than complexifying the entire structure. This selective parameter optimization achieves high binding affinity (pEC50 ≥ 6.0) while preserving ease of manufacture.
Data Source
AI summary
The present invention relates to a chemical compound; a peptide; a Carbonic Anhydrase IX (CAIX) binding compound; a CAIX binding peptide; a composition comprising the compound; a composition comprising the CAIX binding compound; a composition comprising the peptide; a composition comprising the CAIX peptide; the compound, CAIX binding compound, the peptide, the CAIX peptide and the compositions, respectively, for use in a method for the diagnosis of a disease; the compound, the CAIX binding compound and the compositions, respectively, for use in a method for the treatment of a disease; the compound, the CAIX binding compound, the peptide, the CAIX peptide and the compositions, respectively, for use in a method of diagnosis and treatment of a disease; the compound, the CAIX binding compound, the peptide, the CAIX peptide, and the compositions, respectively, for use in a method for delivering a radionuclide to a CAIX expressing tissue; a method for the diagnosis of a disease using the compound, the CAIX binding compound, the peptide, the CAIX peptide and the compositions, respectively; a method for the treatment of a disease using the compound, the CAIX binding compound, the peptide, the CAIX peptide and the compositions, respectively; a method for the diagnosis and treatment of a disease using the compound, the CAIX binding compound, the peptide, the CAIX peptide and the compositions, respectively; a method for the delivery of a radionuclide to a CAIX expressing tissue using the compound, the CAIX binding compound, the peptide, the CAIX peptide and the compositions, respectively.