Solubility Tags for DNA-Encoded Libraries in Organic Solvents
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Solution Overview
Problem
Current DNA-encoded library (DEL) technologies face challenges in generating distinguishable, durable, and soluble DNA tags for organic solvents, due to the limitations of DNA compatibility with organic chemistry reactions.
Innovation Solution
A system for identifying oligonucleotides with high ligation efficiency, involving a substrate for attaching accessory oligonucleotides, and using detectable moieties for recognizing and detecting ligation between these oligonucleotides, allowing for the tagging and solubilization of DNA-encoded libraries in organic solvents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If DNA tags are used in DNA-encoded libraries, then the library can be interrogated through PCR amplification and Next Generation Sequencing, but DNA is insoluble in anhydrous organic solvents which limits chemical reaction compatibility
Solution Approach 1:
The patent introduces a solubility tag as an intermediary component attached to the DNA barcode. This solubility tag acts as a mediator that enables the DNA-conjugated molecule to dissolve in organic solvents without compromising the DNA's functionality for PCR amplification and sequencing. The solubility tag bridges the incompatibility between DNA's hydrophilic nature and the hydrophobic organic solvent environment required for certain chemical reactions.
Solution Approach 2:
The patent creates a composite structure consisting of three main components: the DNA barcode, the solubility tag, and the chemical compound. This composite material combines the properties of each component - the DNA provides encoding capability, the solubility tag provides organic solvent compatibility, and the chemical compound provides the desired chemical properties. The composite nature allows the system to function in organic solvents while maintaining DNA's information-carrying capacity.
2Measurement precision
If multiple DNA fragments are assembled sequentially by DNA ligation to create unique DNA labels, then each molecule can be tagged with specific DNA barcodes, but ligation efficiency varies across different tags affecting decoding accuracy
Solution Approach 1:
The patent performs preliminary characterization of DNA tag ligation efficiency before using them in the final library construction. By pre-assessing which tags ligate efficiently and which do not, the method allows for the selection and optimization of tag sequences. This preliminary action prevents the inclusion of poorly ligating tags in the final library, thereby ensuring high decoding accuracy without sacrificing productivity.
Solution Approach 2:
The patent implements a feedback mechanism where ligation efficiency data from preliminary experiments is used to inform subsequent library construction decisions. Tags that show poor ligation efficiency are identified and either modified or excluded from the final library. This feedback loop ensures that only high-performing tags are used, maintaining both high ligation efficiency and high decoding accuracy in the final DNA-encoded library.
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
The system enhances the quality and solubility of DNA-encoded libraries by normalizing ligation efficiencies across tags, improving decoding accuracy, and enabling chemical reactions in organic solvents, thereby expanding the chemical space accessible by DEL technology.
Implementation Method 1
ligating the intermediary test oligonucleotide molecule to the first accessory oligonucleotide and the second accessory oligonucleotide
Implementation Method 2
a second accessory oligonucleotide comprising a moiety for recognition by a detectable moiety
Data Source
AI summary
Disclosed herein are compositions and methods for detecting oligonucleotide molecules that can be ligated with high efficiency, and methods of using the oligonucleotides to tag DNA encoded libraries and to modify existing DNA encoded libraries to incorporate new functionalities. Also disclosed are compositions for increasing DNA solubility in non-aqueous solvents and assay systems for detecting compounds or conditions that increase the solubility or durability of DEL.