Controlled Pore Glass Solid Support for Nucleic Acid Synthesis
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Solution Overview
Problem
Current methods for synthesizing nucleic acid sequences face challenges such as instability in biological media, poor delivery to target cells, and adverse events due to impurities like partially protected and shorter DNA or RNA sequences, which hinder the clinical application of nucleic acid-based drugs.
Innovation Solution
A solid support structure, specifically controlled pore glass (CPG) with hexaethylene glycol spacers, is used for solid-phase synthesis to reduce process-related impurities and improve the purity of nucleic acid sequences, enhancing their stability and delivery efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If phosphoramidite-based synthesis is used to produce synthetic DNA and RNA sequences, then manufacturing efficiency is improved, but process-related impurities such as partially protected and shorter sequences are generated
Solution Approach 1:
The patent applies preliminary action by pre-installing a removable blocking group on the solid support before synthesis begins. This blocking group prevents impurity formation during the synthesis process itself, rather than requiring post-synthesis purification. The blocking group is removed only after the complete nucleic acid sequence is synthesized, ensuring full-length products are formed first.
Solution Approach 2:
The patent extracts the problematic element (the blocking group) from the synthesis process at a specific stage. The blocking group is introduced initially to prevent impurity formation, then selectively removed after synthesis completion to release the pure full-length nucleic acid sequence, separating the purification step from the synthesis steps.
2Reliability
If synthetic DNA sequences are administered to patients, then therapeutic effects are achieved, but adverse events such as immune responses and off-target activities occur due to impurities
Solution Approach 1:
The blocking group is installed in advance on the solid support to prevent the formation of harmful impurities during synthesis. This preliminary protective measure ensures that only full-length, correctly protected sequences are synthesized, eliminating the source of adverse events before they can occur.
Solution Approach 2:
The blocking group acts as a preliminary anti-action by preventing the formation of shorter and partially protected sequences that would cause immune responses and off-target activities. By blocking the formation of these harmful impurities during synthesis, the method prevents subsequent adverse therapeutic events.
3Productivity
If shorter than full-length DNA sequences are present in the product, then manufacturing yield is improved, but safety concerns arise due to potential immune responses and off-target activities
Solution Approach 1:
The blocking group is pre-installed to prevent shorter sequence formation during synthesis. By blocking premature release or incomplete synthesis, the method ensures that only full-length sequences are produced, eliminating safety concerns while maintaining yield of the desired full-length product.
Solution Approach 2:
The blocking group provides preliminary anti-action by preventing the formation of harmful shorter sequences that would cause immune responses. This preventive measure ensures high yield of safe, full-length therapeutic sequences without generating harmful byproducts.
Data Source
AI summary
Disclosed herein are embodiments of a solid support suitable for synthesizing nucleic acid sequences. The solid support may have a structure according to Formula I, where CPG is controlled pore glass, and m, n, x, y, R1 and R2 are as defined herein.Also disclosed are methods for making and using the solid support, kits including solid support, and a universal linker phosphoramidite suitable for use in the solid support.