Polyoxyethylene Derivatives for Polypeptide Conjugates
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Solution Overview
Problem
Current methods for extending the half-life of biofunctional molecules in the body using polyoxyethylene derivatives result in short degradation times and reduced pharmacological efficacy due to rapid interaction with endogenous molecules and receptors, leading to unfavorable effects such as decreased pharmacological action and altered intracorporeal dynamics.
Innovation Solution
A polyoxyethylene derivative with a specific molecular weight range and divalent spacer structure is used to form a conjugate with polypeptides, allowing for prolonged degradation under physiological conditions, thereby releasing the biofunctional molecule over an extended period.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If biofunctional molecules are chemically modified with water-soluble polymers such as PEG, then the half-life in blood is extended and toxicity is reduced, but the pharmacological action decreases due to formation of hydration layer and shielding effect
Solution Approach 1:
The patent applies preliminary action by introducing a degradable linker component during the conjugation process that will subsequently cleave under physiological conditions to release the active biofunctional molecule. This preliminary incorporation of a cleavable bond allows the system to first achieve extended circulation half-life through PEGylation, then automatically restore full pharmacological activity through in vivo degradation of the linker, thus resolving the contradiction between extended duration and maintained efficacy
Solution Approach 2:
The patent utilizes parameter changes by designing a linker with specific degradation kinetics that change over time. The linker initially maintains the PEG-biofunctional molecule conjugate stable in circulation (extended half-life), then undergoes controlled degradation under physiological conditions to release the active molecule (restored pharmacological action). This temporal parameter change in bond stability resolves the contradiction between extended duration and maintained efficacy
2Reliability
If a prodrug formation method with temporary bonds is used to release biofunctional molecules, then the pharmacological action is improved, but the degradation half-life becomes too short (e.g., 12-18 hr for aminal bonds)
Solution Approach 1:
The patent applies parameter changes by selecting and optimizing the linker chemistry to achieve the desired degradation half-life range. Instead of using rapidly degrading aminal bonds (12-18 hr), the invention employs linkers with modified chemical parameters that degrade at a controlled rate (1-30 days), thereby extending the duration of action while maintaining the prodrug mechanism that restores pharmacological activity
3Reliability
If the degradation rate of the temporary bond is increased to release biofunctional molecules faster, then the pharmacological action is enhanced, but the extension of half-life in blood is reduced
Solution Approach 1:
The patent applies preliminary action by incorporating a stabilizing PEG component that initially protects the biofunctional molecule from rapid degradation and clearance, extending half-life. The degradable linker is designed to remain stable during circulation but cleave under specific physiological conditions, thereby preliminarily establishing extended duration while preparing for subsequent pharmacological activation
Data Source
AI summary
Polyoxyethylene derivatives represented by the following formula (1) provided by the present invention:wherein the symbols in the formula are as defined in the specification, can form conjugates with polypeptide that can be degraded over a long time under physiological conditions to release the polypeptide.