Modified TNFRI Polypeptide Protease Resistance
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Solution Overview
Problem
Current human tumor necrosis factor receptor-I (TNFRI) polypeptides have limitations in binding ability to TNF and are susceptible to protease degradation, leading to short half-life and reduced bioavailability, especially in the gastrointestinal tract and blood, which hampers their effectiveness in treating TNF-mediated diseases.
Innovation Solution
A modified TNFRI polypeptide with specific amino acid substitutions, such as L68V/S92I/H95F/R97P/H98A, is developed to enhance binding affinity to TNF and increase protease resistance, allowing for improved stability and bioavailability, which can be produced in microbial or animal cells without the need for sugar chain modifications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type TNFRI polypeptide is used, then it can bind to TNF, but it has low binding affinity and is susceptible to protease degradation
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid residues in the TNFRI polypeptide sequence. Five specific positions are targeted for substitution: position 68 (Leu to Val), position 92 (Ser to Ile), position 95 (Glu to Phe), position 97 (Arg to Pro), and position 98 (His to Ala). These parameter changes at the molecular level result in improved binding affinity to TNF and increased resistance to protease degradation, directly resolving the technical contradiction between binding reliability and protease susceptibility.
2Reliability
If TNFRI polypeptide is administered, then it can control TNF levels, but it has short half-life and reduced bioavailability
Solution Approach 1:
The patent employs parameter changes by substituting five specific amino acid residues in the TNFRI polypeptide. These modifications (L68V, S92I, E95F, R97P, H98A) collectively enhance the polypeptide's stability against proteolytic degradation and improve its binding affinity to TNF. The resulting modified polypeptide exhibits extended half-life and improved bioavailability while maintaining its ability to control TNF levels, thereby resolving the contradiction between therapeutic reliability and duration of action.
3Ease of operation
If oral formulation is used, then it can improve patient compliance, but TNFRI is degraded in gastrointestinal tract
Solution Approach 1:
The patent applies parameter changes by modifying five critical amino acid positions in the TNFRI polypeptide sequence. These substitutions (particularly S92I, E95F, and R97P) confer enhanced protease resistance, enabling the polypeptide to withstand the harsh gastrointestinal environment. This allows the development of oral formulations that maintain therapeutic efficacy while improving patient compliance, resolving the contradiction between ease of administration and resistance to gastrointestinal degradation.
Data Source
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AI summary
Provided is a modified human tumor necrosis factor receptor-1 polypeptide or a fragment thereof that binds to a tumor necrosis factor in vivo or ex vivo. The modified human tumor necrosis factor receptor-1 polypeptide or fragment exhibits improved ability to bind tumor necrosis factor and resistance to proteases.