Universal Adaptor Oligonucleotides for DNA-Encoded Library Synthesis
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Solution Overview
Problem
Current methods for encoding DNA-encoded chemical libraries require the synthesis of multiple oligonucleotides for each building block, making it inefficient for libraries with three or more sets of building blocks, and lack a general and economical approach for encoding nucleic acid-encoded chemical libraries.
Innovation Solution
A method involving the use of adaptor oligonucleotides that hybridize with both nucleic acid strands and identifier oligonucleotides to form partially double-stranded complexes, allowing for the efficient and economical synthesis of nucleic acid-encoded chemical libraries by incorporating identifier oligonucleotides into the nucleic acid strands, reducing the number of oligonucleotides required.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If multiple oligonucleotides are synthesized for each building block using current encoding methods, then the chemical library can be encoded with identifier oligonucleotides, but the synthesis becomes inefficient and costly when three or more sets of building blocks are used
Solution Approach 1:
A single universal adapter oligonucleotide sequence is designed that can hybridize with multiple different identifier oligonucleotides encoding different building blocks. This universal adapter serves multiple functions: it facilitates ligation with different identifiers, enables pooling of library members, and maintains encoding accuracy across all building block types without requiring separate adapter sequences for each identifier.
Solution Approach 2:
The adapter oligonucleotide acts as an intermediary between the identifier oligonucleotides and the library members. It provides a common interface that allows diverse identifier sequences to be ligated to library members through a unified mechanism, simplifying the encoding process and enabling efficient pooling without compromising identification accuracy.
2Adaptability or versatility
If traditional encoding procedures are used with multiple building blocks, then comprehensive chemical diversity is achieved, but the number of oligonucleotides required increases significantly
Solution Approach 1:
The universal adapter sequence enables a single oligonucleotide to interface with multiple identifier types, reducing the total number of oligonucleotide species required. This maintains the ability to encode diverse chemical building blocks while simplifying the oligonucleotide inventory needed for library construction.
Solution Approach 2:
Library members containing different building blocks are pooled together using the universal adapter sequence as a common handle. This merging approach consolidates what would otherwise require separate handling procedures, reducing operational complexity while preserving the diversity of chemical structures in the library.
3Loss of information
If identifier oligonucleotides are ligated to nucleic acid strands for each building block, then the identity of chemical moieties is encoded, but the process becomes time-consuming and resource-intensive
Solution Approach 1:
The universal adapter oligonucleotide serves as a mediator that enables rapid ligation of identifier sequences to library members. It provides a standardized interface that accelerates the encoding process by eliminating the need for multiple specialized ligation protocols, while ensuring accurate preservation of building block identity information through faithful hybridization and ligation.
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 the production of libraries with a diverse population of pharmacophores, allowing for the identification of candidate binding agents with improved characteristics, and facilitates the screening of large numbers of pharmacophores by encoding the identity of chemical moieties directly into the nucleic acid strands.
Implementation Method 1
adaptor oligonucleotides, such that the adaptor oligonucleotides hybridize to both the nucleic acid strands and the identifier oligonucleotides to form partially double-stranded trimeric complexes
Implementation Method 2
ligating the nucleic acid strands to the identifier oligonucleotides in the partially double-stranded complexes, such that the identifier oligonucleotides are incorporated into the nucleic acid strands
Data Source
AI summary
This invention relates to the synthesis of nucleic acid-encoded chemical libraries using common adaptor sequences. Nucleic acid strands coupled to chemical moieties may be contacted with identifier oligonucleotides comprising coding sequences encoding the chemical moieties and an adaptor oligonucleotides, such that the adaptor oligonucleotide hybridizes to both the nucleic acid strands and the identifier oligonucleotides to allow ligation of the identifier oligonucleotides to the nucleic acid strands. The adaptor oligonucleotide is then removed. Nucleic acid-encoded chemical libraries, and methods of producing or screening such libraries are provided.