FGF2 Variants With N-Terminal Deletions For Receptor Selectivity
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Solution Overview
Problem
Current FGF variants lack receptor selectivity, leading to non-specific activation of FGFR subtypes, which is detrimental for tissue repair and regeneration, as well as clinical applications such as wound healing and bone regeneration, due to their redundant signaling network.
Innovation Solution
Development of N-terminal modified FGF2 and FGF4 polypeptides with specific truncations and amino acid substitutions that enhance receptor selectivity, allowing for selective activation of one or two FGFR subtypes while maintaining or altering activity levels by a factor of at least two compared to wild-type proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If wild-type FGF variants are used, then broad receptor activation occurs, but receptor selectivity is poor leading to non-specific signaling
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions at defined positions (e.g., position 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155) within the FGF polypeptide sequence. These localized modifications alter the interaction interface with specific FGFR subtypes, enabling selective activation of desired receptors while reducing activation of others, thus achieving both adaptability and reliability.
Solution Approach 2:
The patent employs parameter changes by systematically varying amino acid residues at multiple positions in the FGF sequence. Each substitution changes the biochemical parameters (charge, hydrophobicity, steric properties) of the ligand, which in turn modifies the binding affinity and selectivity profile across different FGFR subtypes. This parametric optimization allows tuning of receptor selectivity while maintaining reliable specific signaling activation.
2Reliability
If FGF variants with improved receptor selectivity are developed, then targeted biological activities are enhanced, but the complexity of polypeptide design and optimization increases
Solution Approach 1:
The patent applies segmentation by dividing the FGF polypeptide into distinct functional regions and systematically modifying specific segments. The approach involves segmenting the design process into identifying key positions for substitution, selecting appropriate amino acid replacements, and evaluating their impact on receptor selectivity. This segmented methodology manages design complexity by breaking down the overall optimization task into manageable, systematic steps.
Solution Approach 2:
The patent manages design complexity through systematic parameter changes at defined positions rather than random modifications. By establishing a structured framework for substituting amino acids at specific positions and evaluating their effects on receptor binding, the complexity is transformed from an intractable optimization problem into a systematic screening process with predictable outcomes.
Data Source
AI summary
The present invention relates to the design, manufacture and use of fibroblast growth factor (FGF) polypeptides having improved receptor specificity. In particular, the invention relates to isolated FGF2 polypeptides comprising a truncated N-terminus and optionally N-terminal amino acid substitutions. The present invention provides polypeptides, nucleic acids encoding the polypeptides, compositions comprising same and methods for use thereof.