Cyclic CTLA-4 Peptides for Specific Checkpoint Blockade
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Solution Overview
Problem
Existing small molecule drugs and antibody drugs face challenges such as toxicity, low specificity, difficulty in targeting intracellular molecules, and high manufacturing costs, while no middle molecule drugs effectively inhibit CTLA-4 function for immune checkpoint modulation.
Innovation Solution
Development of cyclic peptides through ribosome display technology, optimized for S—S bond formation, which specifically bind to CTLA-4 and inhibit its interaction with CD80, utilizing various molecular chaperones and affinity maturation to identify high-affinity binders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If small molecule drugs are used, then manufacturing cost is low and administration is easy, but toxicity and side effects increase due to low specificity
Solution Approach 1:
The patent changes the molecular size parameter from small molecule to middle molecule (peptide), and introduces cyclic structure to enhance specificity. This resolves the contradiction by achieving both reasonable manufacturability and reduced toxicity through improved target specificity.
Solution Approach 2:
The patent creates a cyclic peptide structure that combines the advantages of peptides (specificity, stability) while maintaining middle-molecule characteristics. This composite approach achieves balanced performance between manufacturability and safety.
2Reliability
If antibody drugs are used, then specificity and efficacy are high, but manufacturing cost is high and oral administration is difficult
Solution Approach 1:
The patent segments the large antibody molecule into a smaller cyclic peptide structure that maintains binding specificity. This segmentation achieves the reliability of antibodies while improving manufacturability and administration characteristics.
Solution Approach 2:
The patent changes the molecular size parameter from large (antibody) to middle (cyclic peptide), making oral administration feasible while maintaining sufficient specificity through the cyclic structure and targeted binding sites.
3Ease of manufacture
If linear peptides are used, then ease of synthesis is high, but stability and membrane permeability are low
Solution Approach 1:
The patent transforms the linear peptide into a cyclic structure, introducing curvature to the molecular architecture. This cyclic configuration enhances stability and membrane permeability while maintaining synthesis feasibility through established peptide cyclization methods.
4Device complexity
If conventional selection methods are used, then workflow is simple, but obtaining high-affinity binders is difficult
Solution Approach 1:
The patent incorporates affinity maturation as a preliminary action in the selection workflow, systematically improving binder affinity through iterative mutagenesis and selection. This preliminary optimization ensures high-affinity binders are obtained while maintaining a manageable workflow.
Solution Approach 2:
The patent implements feedback mechanisms in the selection process, using binding data to guide subsequent selection rounds and affinity maturation steps. This feedback loop efficiently identifies high-affinity binders by continuously optimizing based on measured performance.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The cyclic peptides effectively inhibit CTLA-4 function, offering a potential immune checkpoint inhibitor for therapeutic applications, particularly in treating cancers by modulating the immune system.
Implementation Method 1
the cyclic peptide binds specifically to CTLA-4 and inhibits the interaction between CTLA-4 and CD80
Implementation Method 2
the concentration of oxidants and reductants optimal for S—S bond formation can be freely set
Data Source
AI summary
The present invention provides a cyclic peptide which comprises the amino acid sequence represented by formula (I)X1-His-Pro-X4-Leu-X6-X7-X8-Ser-X10-His-Phe (I)in the cycle and has an activity to specifically bind to human CTLA-4, wherein X1, X4, X6, X7, X8 and X10 are each independently any amino acid.