Modified DNA-Encoded Libraries Using 7-Deazapurines
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current DNA-encoded chemical libraries face limitations due to the chemical lability of DNA, requiring specific reaction conditions that often lead to DNA degradation, and the need for DNA compatibility with small molecule synthesis, which restricts the design and synthesis of drug-like structures.
Innovation Solution
The use of 7-deazapurines and/or 7-deaza-8-azapurines as purine bases in nucleic acid moieties allows for the synthesis of conjugate molecules that are tolerant to a broad spectrum of reaction conditions, including strong acids and transition metals, enabling the formation of drug-like structures and stable DNA-barcode conjugates.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If DNA is used as the nucleic acid moiety in DNA-encoded chemical libraries, then the DNA-tag can be identified and quantified by PCR-amplification and sequencing, but the DNA integrity is compromised by depurination under many reaction conditions required for small molecule synthesis
Solution Approach 1:
The patent applies parameter changes by substituting the chemical structure of purine bases with modified variants (7-deazapurines and 7-deaza-8-azapurines) that have altered stability properties. These modified bases resist depurination under acidic and metal-catalyzed conditions while maintaining compatibility with PCR amplification and sequencing, thus resolving the contradiction between DNA integrity and synthesis condition compatibility
Solution Approach 2:
The patent creates a composite nucleic acid system combining modified purine bases (7-deazapurines and 7-deaza-8-azapurines) with standard pyrimidine nucleotides. This composite structure provides both the enhanced chemical stability needed for diverse synthesis conditions and the sufficient compatibility for downstream PCR and sequencing applications
2Reliability
If standard DNA composition is used, then PCR amplification and sequencing can be performed, but the DNA is degraded under acidic conditions and upon incubation with Lewis acids under forcing reaction conditions
Solution Approach 1:
The patent converts the typically harmful effect of acidic conditions and metal catalysts that cause depurination into beneficial opportunities for performing diverse chemical transformations. The modified purine bases enable the use of strong acids and Lewis acids as reaction conditions for small molecule synthesis while preventing DNA degradation, thus transforming harmful factors into usable reaction conditions
3Reliability
If DNA compatibility is prioritized in library synthesis, then DNA integrity is maintained, but the design of drug-like structures is restricted due to limited reaction conditions
Solution Approach 1:
The patent achieves universality by designing a nucleic acid moiety that serves multiple functions: it remains compatible with PCR amplification and sequencing, withstands diverse synthesis conditions including strong acids and metal catalysts, and enables the formation of drug-like structures. The modified purine base system provides a universal platform that accommodates both biological compatibility and chemical versatility
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 synthesis of a diverse range of drug-like small molecule structures and allows for high-fidelity PCR amplification and sequencing, overcoming the limitations of DNA degradation in existing DNA-encoded library synthesis methods.
Implementation Method 1
The main DNA degradation reaction is caused by depurination, i.e. the cleavage of purine bases from the DNA oligomer. DNA can be depurinated under acidic conditions and upon incubation with Lewis acids under forcing reaction conditions such as elevated temperature.
Implementation Method 2
the DNA-tag of the relevant hit compounds can be identified and quantified by PCR-amplification and sequencing
Implementation Method 3
the DNA-tag of the relevant hit compounds can be identified and quantified by PCR-amplification and sequencing
Implementation Method 4
said conjugates comprise a small organic molecule covalently coupled to a nucleic acid moiety
Data Source
AI summary
A compound library may include a plurality of conjugate molecules, said conjugates comprising a small organic molecule covalently coupled to a nucleic acid moiety. The nucleic acid moiety may include or consist of 7-deazapurines and/or 7-deaza-8-azapurines, and, optionally, modified pyrimidine nucleotides and/or unmodified pyrimidine nucleotides. Further, a library for screening compounds binding to a target molecule and methods of synthesizing said library is also disclosed.