FGF21 Derivatives With Fatty Acid Side Chains
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Solution Overview
Problem
FGF21 suffers from in vivo instability due to proteolysis, leading to significant loss of activity, particularly in the C-terminal region, and existing engineering methods to protect against degradation result in reduced potency.
Innovation Solution
Development of FGF21 derivatives with a side chain covalently attached to specific positions, including 167, 169, 170, 171, 172, 173, 174, 175, 180, or 181, using a linker and protractor connected via an amide bond, which enhances stability and potency by forming a thioether bond with the cysteine residue.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If the C-terminal region of FGF21 is engineered to protect against degradation, then stability is improved, but potency is reduced or lost
Solution Approach 1:
The patent applies local quality by making a specific localized modification at position 181 of the FGF21 protein. Instead of engineering the entire C-terminal region, only a single cysteine residue at position 181 is modified with a fatty acid side chain. This localized modification protects against degradation at the vulnerable C-terminal end while preserving the integrity and function of the rest of the protein structure, thereby maintaining potency.
Solution Approach 2:
The patent creates a composite structure by combining the FGF21 protein with a fatty acid side chain through a thioether bond at position 181. This composite molecule integrates the biological activity of FGF21 with the stabilizing properties of the fatty acid chain, resulting in a molecule that exhibits both enhanced stability against proteolysis and maintained biological potency.
2Stability of the object's composition
If FGF21 is PEGylated at position 180 or fused with Fc at the C-terminus, then stability is improved, but potency is dramatically reduced
Solution Approach 1:
The patent applies local quality by making a specific localized modification at position 181 of the FGF21 protein. Instead of engineering the entire C-terminal region, only a single cysteine residue at position 181 is modified with a fatty acid side chain. This localized modification protects against degradation at the vulnerable C-terminal end while preserving the integrity and function of the rest of the protein structure, thereby maintaining potency.
3Reliability
If endogenous FGF21 circulates in the body, then metabolic regulation occurs, but in vivo instability due to proteolysis causes significant loss of activity
Solution Approach 1:
The patent applies preliminary anti-action by pre-protecting the FGF21 protein against proteolytic degradation before it encounters enzymes in the body. The fatty acid side chain at position 181 creates a steric and chemical barrier that prevents proteases from accessing and cleaving the C-terminal region, thereby preserving the protein's activity throughout its circulation and eliminating the need for continuous replenishment.
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 FGF21 derivatives exhibit high potency and a protracted pharmacokinetic profile, maintaining activity and extending terminal half-life when administered, addressing the instability and potency issues of native FGF21.
Implementation Method 1
The side chain is covalently attached to the sulfur atom of the cysteine residue to which the side chain is attached
Implementation Method 2
The protractor and the linker are connected via an amide bond
Data Source
AI summary
The invention relates to a derivative of a FGF21 protein having a cysteine residue at a position corresponding to position 167, 169, 170, 171, 172, 173, 174, 175 and in particular position 180 or position 181 of mature human FGF21 and derivatives thereof having a side chain attached to this cysteine. The FGF21 derivatives of the invention display high potency towards the FGF receptors. The invention also relates to pharmaceutical compositions comprising such FGF21 derivatives and pharmaceutically acceptable excipients, as well as the medical use of the FGF21 derivatives.