Spatially Addressed Ligand Libraries With Cleavable Decoding Linkers
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Solution Overview
Problem
Existing encoded split pool synthesis methods for molecular arrays face limitations in library size, decoding efficiency, and interference issues, restricting the number of 'hits' that can be identified in a cost-effective manner.
Innovation Solution
The use of microparticles covalently attached to ligand and nucleic acid domains through different linkers, where the nucleic acid linker is cleavable, allowing for decoding and mapping of ligand binders on a solid support.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If encoded split pool synthesis is used to generate large chemical libraries, then the number of library members increases, but the number of decodable hits that can be identified in a cost-effective manner decreases due to serial decoding strategies
Solution Approach 1:
The patent divides the library screening process into parallel decoding streams by assigning different encoding schemes to different particle subsets. This allows simultaneous decoding of multiple library members rather than serial decoding, thereby maintaining high productivity while supporting large library sizes.
Solution Approach 2:
The patent introduces a spatial dimension to the decoding process by using particles of different sizes or types that can be decoded in parallel. This dimensional approach enables cost-effective identification of multiple hits simultaneously, resolving the contradiction between library size and decoding efficiency.
2Productivity
If ligand density on particles is increased to improve screening efficiency, then the number of detectable ligand binders increases, but the surface chemistry environment around ligands interferes with assay performance
Solution Approach 1:
The patent creates distinct surface chemistry environments for different particle types, where each particle subset has optimized local chemistry that does not interfere with ligand binding assays. This local differentiation allows high ligand density while maintaining assay reliability through appropriate surface chemistry design for each particle type.
3Difficulty of detecting and measuring
If large particles are used for decoding by radio frequency tags or mass spectrometry, then decoding capability is improved, but the number of library members that can be contained decreases
Solution Approach 1:
The patent segments the library into different particle size categories, where smaller particles can be decoded by mass spectrometry and larger particles can be decoded by radio frequency tags. This segmentation allows both decoding methods to operate on appropriate particle sizes, maximizing the total number of library members that can be contained and decoded.
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
Enables the detection of ligand binders with improved decoding efficiency and increased library size, overcoming limitations of existing methods by allowing for more effective screening and identification of hits.
Implementation Method 1
a nucleic acid domain through a second linker, wherein the second linker is cleavable and the first linker is not cleavable under a condition that the second linker is cleavable
Data Source
AI summary
Provided herein are encoded split pool libraries useful, inter alia, for forming highly diverse and dense arrays of ligand domains for screening and detection of a variety of ligand binder molecules. Also provided herein are methods for forming, decoding, binding to, and selectively cleaving the highly diverse and dense arrays of ligand domains.