Cyclic Polypeptides for Ubiquitin Binding and Cell Permeability
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Solution Overview
Problem
Current molecules targeting ubiquitin chains, such as ubistatins, face challenges with poor cell permeability, weak binding affinity, and lack of specificity, making it difficult to effectively interfere with ubiquitin signaling pathways, particularly in cancer therapy.
Innovation Solution
Development of cyclic polypeptides with nanomolar binding affinity to ubiquitin polymers, specifically K48-linked chains, which can penetrate cells and reduce deubiquitination activity, thereby offering a potential therapeutic approach for cancer treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecules like ubistatins are used to target ubiquitin chains, then binding to ubiquitin can be achieved, but cell permeability remains poor and binding affinity is weak
Solution Approach 1:
The invention changes the molecular parameters by transitioning from small molecule ubistatins to cyclic polypeptides with specific amino acid compositions and structures. This parameter change enables simultaneous achievement of nanomolar binding affinity and effective cell permeability, resolving the contradiction between strong binding and cell entry capability
Solution Approach 2:
The invention creates composite molecular structures by designing cyclic polypeptides that combine specific amino acid sequences (including K48-linked ubiquitin chains) with cyclic conformations. This composite structure integrates the benefits of peptide specificity with enhanced stability and cell permeability, overcoming the limitations of simple small molecules
2Adaptability or versatility
If molecules are designed to target specific ubiquitin chain linkages, then specificity improves, but the complexity of molecular recognition increases significantly
Solution Approach 1:
The invention applies local quality by designing cyclic polypeptides with specific local amino acid sequences that recognize particular ubiquitin chain linkages (e.g., K48). Rather than requiring the entire molecule to be complex, only specific local regions are optimized for recognition, simplifying the overall molecular recognition process while maintaining high specificity
Solution Approach 2:
The invention segments the ubiquitin recognition function into distinct modular elements within the cyclic polypeptide structure. Each amino acid or amino acid sequence segment contributes specifically to recognizing different aspects of the ubiquitin chain, allowing the system to handle multiple chain types through modular recognition rather than requiring a single complex binding interface
3Reliability
If cyclic polypeptides are designed for high binding affinity, then deubiquitination activity is reduced, but the ability to penetrate living cells must be maintained
Solution Approach 1:
The invention applies dynamics by designing cyclic polypeptides that can undergo conformational adjustments upon cell entry. The cyclic structure provides stability for high binding affinity, while the dynamic flexibility of the peptide backbone allows adaptation to the cellular environment and penetration through cell membranes, resolving the contradiction between stability and penetrability
Data Source
AI summary
The present invention is directed to a cyclic polypeptide having ubiquitin binding affinity (KD) of 0.1-100 nM. Further provided are methods for reducing deubiquitination activity of a cell, and for treating cancer in a subject in need thereof.