ALEnOmer Aptamer Synthesis via Branching Unit
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Solution Overview
Problem
Aptamers face challenges due to their narrow chemical space, susceptibility to nuclease degradation, and poor cellular uptake, which limits their therapeutic applications, and existing modification strategies are limited in incorporating non-nucleosidic functional modifications.
Innovation Solution
A method for synthesizing aptamer-like encoded oligomers (ALEnOmers) using a branching unit to attach a DNA coding strand to an oligomer, allowing for the incorporation of unnatural monomers and orthogonal protecting groups, enabling the creation of a DNA-encoded library with a high degree of polymerization and improved properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If conventional aptamers are used, then they are easy to synthesize through solid-phase synthesis, but their chemical space is narrow and they suffer from poor cellular uptake and renal clearance
Solution Approach 1:
The patent creates composite oligonucleotide structures by combining natural nucleotides with non-nucleosidic functional modifications. The DNA-encoded library consists of oligonucleotides that incorporate both canonical nucleotides (for synthesis and encoding) and unnatural functional monomers (for enhanced properties), achieving a composite material that retains ease of DNA synthesis while expanding chemical diversity and improving cellular uptake
Solution Approach 2:
The patent applies local quality by incorporating non-nucleosidic functional modifications at specific positions within the oligonucleotide sequence rather than uniformly throughout. The DNA-encoded library allows selective placement of functional monomers at defined locations, enabling local enhancement of properties such as cellular uptake, stability, or binding affinity while maintaining the overall oligonucleotide structure and synthesis compatibility
2Reliability
If existing modification strategies are used, then some properties of aptamers can be improved, but they are limited in incorporating non-nucleosidic functional modifications
Solution Approach 1:
The patent creates a universal platform for incorporating diverse non-nucleosidic functional modifications into oligonucleotides. The DNA-encoded library methodology provides a multi-functional approach that can simultaneously incorporate different types of functional monomers (aromatic, charged, hydrophobic, etc.) at various positions, enabling a single system to address multiple aptamer limitations including stability, cellular uptake, and binding affinity
Solution Approach 2:
The patent systematically varies chemical parameters by incorporating functional monomers with different properties (aromatic rings for pi-stacking, charged groups for electrostatic interactions, hydrophobic moieties for membrane penetration) into the oligonucleotide sequence. This parameter changes approach allows optimization of multiple aptamer properties simultaneously through chemical modification while maintaining synthesis feasibility
Data Source
AI summary
It is provided the synthesis of an aptamer-like encoded oligomer (ALEnOmer), method of producing same and method of preparing a library of ALEnOmes. More particularly, the method of preparing ALEnOmer comprises coupling at least one phosphoramidite monomer with an orthogonal protecting group, and the ALEnOmer produces comprises a DNA coding strand covalently attached to an oligomer through a branching unit, wherein the oligomer has a degree of polymerization at least 5 and is an aptamer.