OB-fold Protein Scaffold Engineering for Stable Binders
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Solution Overview
Problem
Natural proteins are not well-suited for therapeutic or biotechnological applications due to their molecular complexity and instability, making it difficult and expensive to produce antibodies or their derivatives that bind specifically and with high affinity to various targets like proteins, nucleic acids, or carbohydrates.
Innovation Solution
The use of an oligonucleotide/oligosaccharide binding-fold (OB-fold) protein, such as Sac7d, is modified through combinatorial mutation/selection to create variants that bind specifically to different targets, maintaining stability and folding efficiency while altering binding specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If natural proteins are used as binding molecules, then they can bind to targets, but they have molecular complexity and insufficient stability for therapeutic use
Solution Approach 1:
The patent extracts only the essential binding function from natural proteins by using simplified scaffold proteins (such as OB-fold proteins) that lack the complex structural features of natural antibodies while retaining the ability to bind specific targets through engineered binding sites
Solution Approach 2:
The patent changes the structural parameters of the binding molecule by using artificial scaffold proteins with standardized folds (OB-fold) and modifying only the binding interface residues, thereby reducing molecular complexity while maintaining stability and binding capability
2Manufacturing precision
If antibodies are used for binding, then high specificity and affinity can be achieved, but production becomes difficult and expensive
Solution Approach 1:
The patent changes the production parameters by using simplified scaffold proteins that are easier to express and purify compared to full antibodies, while achieving comparable binding specificity through directed evolution of the binding interface
Solution Approach 2:
The patent employs minimalistic scaffold proteins that can be produced cost-effectively and discarded after use, replacing the expensive and complex antibody production system with a more economical approach using small, stable scaffold molecules
3Reliability
If antibody derivatives are used, then binding capability is maintained, but stability is insufficient for therapeutic applications
Solution Approach 1:
The patent changes the stability parameter by using scaffold proteins with inherent structural stability (such as the OB-fold structure with high thermal stability) that maintains binding affinity while providing the stability needed for therapeutic applications
Data Source
AI summary
The present invention pertains to the field of protein engineering, and provides means for obtaining stable molecules that specifically bind to a target selected amongst a large variety of ligands families. In particular, the present invention provides methods for obtaining a molecule specifically binding to a target of interest, through a combinatorial mutation/selection approach with an OB-fold protein as a starting molecule. In particular, the target of interest can be of a different chemical nature form that of the native target of the OB-fold protein used as the starting molecule.