Protein Scaffold Engineering for Stable Binding to Disordered Regions
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Solution Overview
Problem
Existing drug discovery methods focus primarily on structured protein regions, neglecting the functional potential of disordered protein segments, which are underutilized for targeted protein interactions.
Innovation Solution
Development of engineered scaffold proteins and fusion proteins that specifically bind to disordered regions of target peptides, enhancing binding activity, stability, and solubility, and incorporating molecular transporters for targeted drug delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If drug discovery methods focus on structured protein regions, then targeted protein interactions can be established, but disordered protein segments are neglected and their functional potential is underutilized
Solution Approach 1:
The patent applies parameter changes by modifying the binding domain's structural and chemical properties to accommodate disordered regions. Specific amino acid alterations are introduced to enhance binding affinity and stability to disordered protein segments, transforming the binding domain from a structure-oriented design to one that can reliably interact with intrinsically disordered regions while maintaining therapeutic effectiveness
Solution Approach 2:
The invention incorporates dynamics by designing a flexible binding domain that can adapt its conformation to match the disordered structure of target proteins. The binding domain includes flexible linkers and adaptable amino acid sequences that allow dynamic adjustment during binding, enabling reliable interactions with intrinsically disordered regions that lack fixed three-dimensional structures
2Reliability
If engineered scaffold proteins are designed with increased binding affinity to disordered regions, then binding frequency and duration improve, but protein stability and solubility may be compromised
Solution Approach 1:
The patent applies local quality by introducing specific amino acid alterations only in the binding domain while maintaining the structural integrity of the scaffold protein's core regions. This localized modification approach enhances binding affinity to disordered regions without compromising the overall stability and solubility of the engineered scaffold protein, as the changes are confined to specific functional areas rather than affecting the entire protein structure
3Duration of action of moving object
If engineered scaffold proteins are designed with increased binding affinity to disordered regions, then binding duration improves, but immunogenicity may increase
Solution Approach 1:
The patent applies parameter changes by systematically altering amino acid sequences in the binding domain to optimize binding duration while controlling immunogenicity. Specific amino acid alterations are made to enhance binding affinity and duration, while concurrent modifications are made to reduce immunogenicity through changes in surface properties and amino acid composition, achieving both extended binding duration and reduced immune recognition
Data Source
AI summary
The disclosure provides proteins that can be used as scaffolds to bind a specific target, including specific proteins or peptides of interest, as well as fusion proteins with the scaffolds. Such proteins or peptides of interest may include disordered regions. The invention also relates to various uses of the scaffold, including diagnostics, therapeutics, detection reagents, and vaccines. The protein scaffolds can be tailored to specifically bind a target using the methods described herein.