VEGF-D Dimer Interface Mutations for Angiogenesis
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Solution Overview
Problem
The existing VEGF-D proteins have limited covalent dimerization and activity at VEGF receptors, which hinders their effectiveness in promoting angiogenesis, a crucial process for therapeutic applications such as treating ischemia and coronary artery disease.
Innovation Solution
Modifying the VEGF-D protein by altering the dimer interface through specific amino acid mutations, such as replacing Cys25 with Leu, Ile, or Val, increases covalent dimer formation and enhances its activity at VEGF receptors, promoting more effective angiogenesis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If VEGF-D protein is used to promote angiogenesis, then therapeutic effect is improved, but covalent dimerization capability is insufficient which limits receptor activity
Solution Approach 1:
The patent applies parameter changes by mutating specific amino acid residues at the dimer interface of VEGF-D protein. The Cys25Leu mutation and other interface mutations alter the chemical and physical parameters of the dimerization interface, transforming the weak non-covalent interactions into strong covalent disulfide bonds, thereby resolving the contradiction between limited dimerization capability and therapeutic effectiveness
Solution Approach 2:
The patent extracts and modifies the critical dimer interface region of VEGF-D protein. By identifying and mutating specific residues (Cys25, Cys44, Cys53) at the dimer interface, the invention isolates and enhances the covalent dimerization function, separating this critical function from the rest of the protein structure to improve overall therapeutic activity
2Reliability
If amino acid mutations are introduced to increase covalent dimerization, then VEGF receptor activity is enhanced, but protein structure complexity increases
Solution Approach 1:
The patent applies local quality by introducing mutations only at the specific dimer interface region rather than throughout the entire protein structure. The Cys25Leu mutation and other interface mutations are localized changes that specifically enhance covalent dimerization without altering the overall fold or distant functional regions of the VEGF-D protein, thus minimizing structural complexity increase while maximizing receptor activity
Solution Approach 2:
The patent changes local parameters at the dimer interface by mutating specific amino acid residues. These localized parameter changes (amino acid substitutions) modify the chemical properties and bonding capabilities at the interface, enhancing covalent dimerization and VEGF receptor activity without requiring global structural modifications
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 modified VEGF-D protein exhibits a higher dimer to monomer ratio and significantly increased activity at VEGF receptors, making it a more effective mediator of therapeutic angiogenesis compared to the wild-type protein.
Implementation Method 1
VEGF-D proteins have limited covalent dimerization... replacing Cys25 with Leu, Ile, or Val, increases covalent dimer formation
Data Source
AI summary
The present invention is a VEGF-D protein, containing one or more amino acid mutations at the dimer interface, and their use in therapy, particularly in the promotion of angiogenesis.