Releasable Conjugates via 3′ Phosphotriester Decomposition
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Solution Overview
Problem
Current methods for designing and using releasable conjugates of biologically active molecules with aliphatic polymers, such as polyethylene glycol, lack control over the release kinetics and often require extensive modification of linker moieties, leading to residual polymer traces after drug release.
Innovation Solution
The development of conjugates where a biologically active molecule is indirectly bound to an aliphatic polymer through a linking moiety, utilizing 3′ phosphotriester groups that decompose upon intramolecular nucleophilic attack, allowing for controlled release with minimal residual polymer, and allowing for modifiable trigger moieties like enzyme-labile or pH-labile groups for precise kinetics control.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If 3′ phosphotriester groups are used for drug release, then release kinetics can be controlled, but residual polymer traces remain after drug release
Solution Approach 1:
The patent extracts the trigger moiety E from direct polymer attachment, positioning it on the ribonucleoside scaffold instead. This allows the polymer to be released completely upon trigger decomposition, eliminating residual polymer traces while maintaining controlled release kinetics through the phosphotriester group decomposition mechanism
Solution Approach 2:
The ribonucleoside scaffold with 3′ phosphotriester group serves as an intermediary structure between the polymer and trigger moiety. The phosphotriester group decomposes upon intramolecular nucleophilic attack, mediating the release of both the trigger moiety and the polymer, thereby achieving complete polymer removal without residual traces
2Reliability
If extensive modification of linker moieties is performed, then releasable conjugates can be achieved, but device complexity increases
Solution Approach 1:
The patent creates a universal ribonucleoside-based platform where the 3′ phosphotriester group can be attached to various biologically active molecules through different trigger moieties E. This multi-functional approach allows the same core structure to serve multiple release mechanisms (enzymatic, pH-labile, etc.) without requiring extensive individual modifications for each conjugate
Solution Approach 2:
The conjugate is segmented into distinct functional modules: the polymer attachment point, the ribonucleoside scaffold with 3′ phosphotriester group, and the trigger moiety E. This segmentation allows independent optimization of each module while maintaining overall simplicity, as the core phosphotriester mechanism remains constant across different applications
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
This approach enables controlled and efficient release of biologically active drugs with minimal residual polymer, offering synthetic freedom and improved control over prodrug liberation in vivo, while avoiding extensive modification of each conjugate.
Implementation Method 1
3′ phosphotriester groups of a ribonucleoside are unstable in the presence of free vicinal 2′ hydroxyl moieties and can decompose following intramolecular nucleophilic attack of a 2′ hydroxyl moiety at the 3′ phosphotriester group
Implementation Method 2
The cyclic phosphotriester may be further hydrolyzed at physiological pH resulting in the opening of the 5-membered ring and formation of both isomeric phosphodiesters
Data Source
AI summary
The present application provides compounds of Formula (B):or pharmaceutically acceptable salts thereof, wherein D is a residue of a biologically active drug, which underdo hydrolysis under physiological conditions to release the biologically active drug and which are useful in the treatment of disorders that could be beneficially treated with the drug.