Oligonucleotide-Directed Combinatorial Libraries Without Slow Sorting
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Solution Overview
Problem
Existing methods of synthesizing DNA-encoded libraries face challenges in efficiently sorting libraries of oligonucleotides, leading to slow partitioning on physical hybridization arrays.
Innovation Solution
The method involves forming precursor molecules through reverse transcription and RNA hydrolysis, using charged or uncharged carriers with complementary regions to hybridize with RNA molecules, thereby synthesizing DNA-encoded compounds and libraries without the need for a slow sorting step.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If existing methods of library synthesis are used, then DNA-encoded compounds can be synthesized, but the sorting of oligonucleotide libraries is slow and inefficient
Solution Approach 1:
The patent extracts and eliminates the slow sorting step from the traditional library synthesis workflow. By using a solid support system where oligonucleotides are covalently attached during synthesis, the method removes the need for subsequent sorting operations, directly addressing the time loss problem while maintaining productivity.
Solution Approach 2:
The patent performs the sorting function in advance during the synthesis process itself. By incorporating solid support beads that selectively capture desired oligonucleotide sequences during synthesis, the method prepares the final library configuration before the reaction completes, eliminating the need for post-synthesis sorting and significantly reducing time loss.
2Ease of operation
If physical hybridization arrays are used for partitioning, then oligonucleotide sorting can be achieved, but the process is slow
Solution Approach 1:
The patent replaces the mechanical physical hybridization array system with a chemical solid support-based system. Instead of using physical arrays that require sequential hybridization and washing steps, the invention uses chemically functionalized beads that capture oligonucleotides through covalent bonding during synthesis, dramatically increasing partitioning speed while maintaining operational simplicity.
3Reliability
If traditional synthesis methods are used, then DNA-encoded compounds can be produced, but the overall synthesis efficiency is reduced due to slow sorting
Solution Approach 1:
The patent merges the synthesis and sorting operations into a single integrated process. By combining the oligonucleotide synthesis with simultaneous solid support-mediated sorting, the method eliminates the sequential nature of traditional approaches, improving both the reliability of compound production and the overall synthesis efficiency without compromising either function.
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 enhances the efficiency of DNA-encoded library synthesis by bypassing the slow and inefficient sorting process, allowing for faster and more effective production of DNA-encoded compounds and libraries.
Implementation Method 1
hybridizing the complementary region of the charged carrier to the RNA molecule
Implementation Method 2
reverse transcribing the RNA molecule that is primed by the charged carrier to form a DNA-RNA heteroduplex
Implementation Method 3
performing RNA hydrolysis on the DNA-RNA heteroduplex to form the precursor molecule
Data Source
AI summary
The present disclosure relates to precursor molecules of DNA-encoded compounds, and methods of preparing thereof. In some aspects, provided herein are methods of synthesizing DNA-encoded compounds, and libraries thereof, from precursor molecules and positional building blocks.