Cyclic Peptide Composition for Low-Dose Selective Cancer Cell Killing
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Solution Overview
Problem
Existing CDK4-based peptides for cancer treatment have low specific activity and require high concentrations for efficacy, leading to limited therapeutic potential due to impaired cell uptake and non-specific cell killing.
Innovation Solution
Development of cyclic peptides with non-polar amino acids, such as Dac, Sar, dmPro, and Nap, to enhance cell membrane penetration and cytotoxic activity, specifically targeting cancer cells with sequences like Dac-Arg-Sar-dmPro-Arg-Nap or Dac-Arg-Sar-Nap-Arg-Nap, and optionally flanked by cysteine residues for cyclization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CDK4-based peptides are used for cancer treatment, then they can inhibit cancer cell growth through CDK4 inhibition, but they require high concentrations to achieve efficacy due to low specific activity and impaired cell uptake
Solution Approach 1:
The patent modifies the peptide structure by incorporating non-polar amino acids (Dac, Sar, dmPro, Nap) to change the physicochemical parameters of the peptide, specifically enhancing its hydrophobicity and cell membrane penetration capability. This structural parameter change enables the peptide to achieve effective CDK4 inhibition at lower concentrations, resolving the contradiction between reliability of cancer cell growth inhibition and quantity of substance required.
2Reliability
If high concentrations of CDK4-based peptides are administered to achieve therapeutic effect, then cancer cell growth can be inhibited, but non-specific cell killing occurs leading to side effects
Solution Approach 1:
The patent introduces non-polar amino acid residues at specific positions within the peptide sequence to create local hydrophobic regions that enhance selective interaction with cancer cell membranes. This local quality modification allows the peptide to achieve selective uptake in cancer cells through enhanced membrane penetration, thereby achieving therapeutic effect at lower concentrations and reducing non-specific cell killing and associated side effects.
3Ease of manufacture
If conventional linear peptide structures are used, then they can be synthesized relatively easily, but they exhibit poor cell membrane penetration and low specific activity
Solution Approach 1:
The patent maintains the linear peptide structure for ease of synthesis but modifies the amino acid composition by incorporating non-polar residues (Dac, Sar, dmPro, Nap) to change the peptide's physicochemical parameters. This enables the peptide to achieve enhanced cell membrane penetration and specific activity while retaining the simplicity of conventional peptide synthesis methods, thus resolving the contradiction between ease of manufacture and reliability of specific activity.
Data Source
AI summary
The present invention relates to a cyclic peptide comprising an active region comprising the amino acid sequence X1X2X3X4X5X6 or a salt, derivative, prodrug or mimetic thereof. X2 and X5 are arginine; and either:X1 is (7-methoxy-coumarin-4-yl)-Ala-OH (Dac) and X3, X4 and X6 are any amino acid; orX3 is sarcosine (Sar) and X1, X4 and X6 are any amino acid; orX4 is 5,5-dimethylproline (dmPro) or 3-amino-3-(2-naphthyl)propionic acid (Nap) and X1, X3 and X6 are any amino acid; orX6 is Nap and X1, X3 and X4 are any amino acid.The present invention further relates to a pharmaceutical composition comprising the cyclic peptide and the peptide for use in medicine, and particularly cancer.