Mutated Designer BMP Proteins for Bone Volume
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Solution Overview
Problem
Current BMPs have limitations in their receptor binding affinity and activity, which affects their therapeutic efficacy in tissue regeneration and repair, particularly in bone formation and wound healing, as they require high protein levels for effective biological activity.
Innovation Solution
Designer BMP proteins with specific mutations in type I and type II receptor binding domains, such as those at V33, P36, H39, E83, and S85, are developed to enhance binding affinity to BMP receptors, thereby increasing their biological activity and therapeutic potential at lower protein levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current BMPs are used for therapeutic applications, then bone formation and tissue repair can be achieved, but high protein levels are required which reduces therapeutic effectiveness and increases dosage requirements
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of BMP proteins through site-directed mutagenesis. Specific mutations in the type I and type II receptor binding domains (such as V33M, P36L, H39Q, E83Q, S85T) alter the binding parameters to increase affinity for BMP receptors, thereby enhancing biological activity at lower protein concentrations
Solution Approach 2:
The patent applies local quality by making targeted mutations only in the receptor binding domains rather than the entire protein structure. This preserves the overall protein fold and cystine knot topology while locally optimizing the binding interface to enhance receptor interaction and biological efficacy
2Productivity
If BMP proteins are mutated to enhance receptor binding affinity, then biological activity increases at lower protein levels, but the complexity of protein design and characterization increases
Solution Approach 1:
The patent applies segmentation by dividing the BMP protein into functional domains: the cystine knot core structure that maintains stability, and the receptor binding domains (type I and type II) that are targeted for mutation. This segmentation allows independent optimization of binding affinity while preserving structural integrity
Solution Approach 2:
The patent applies preliminary action by using computational modeling and structural analysis to predict beneficial mutations before experimental testing. The mutations are designed based on prior knowledge of BMP-receptor interaction interfaces, reducing the search space and accelerating the development of high-activity variants
Data Source
AI summary
The invention relates to novel designer osteogenic proteins having altered affinity for a cognate receptor, nucleic acids encoding the same, and methods of use therefor. More preferably, the novel designer osteogenic proteins are designer BMPs and have altered affinity for a cognate BMP receptor. The designer BMPs demonstrate altered biological characteristics and provide potential useful novel therapeutics.