Functional Group-Guided Aptamer Selection for Sterically Hindered Targets

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Solution Overview

Problem

Existing methods struggle to isolate aptamers with appropriate affinities for clinically important low molecular weight targets like leucine and voriconazole, as standard protocols fail to account for structural barriers posed by sterically hindered functional groups.

Innovation Solution

A functional group-guided approach is employed, involving insertion reselection, use of metal complexes as protective groups, and synthesis of simpler analogs to overcome steric barriers, combined with traditional protocols and organic receptor cofactors, to identify high-affinity aptamers.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of manufacture

If standard selection protocols are used to isolate aptamers, then the process is simple and straightforward, but aptamers with appropriate affinities for sterically hindered targets cannot be obtained

Engineering Contradiction:

Improveease of aptamer isolationVSAvoidaptamer affinity for target

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The patent segments the aptamer binding interface into distinct functional group recognition zones. By dividing the recognition site into specific regions that interact with different functional groups (e.g., carbonyl, hydroxyl, aromatic groups), the method enables systematic optimization of affinity for sterically hindered targets while maintaining simplicity in the overall selection protocol.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent applies local quality by creating aptamers with specific local structural features tailored to recognize particular functional groups on the target molecule. Each region of the aptamer is designed with specific nucleotide sequences and structural characteristics that optimize binding to specific functional groups, thereby improving overall affinity for challenging targets.

Inventive Principle:

Principle #3Local quality

2Reliability

If functional group-guided approach with multiple steps is used, then aptamer isolation for previously inaccessible targets becomes possible, but the process complexity increases

Engineering Contradiction:

Improveaptamer isolation success rateVSAvoidselection protocol complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent employs preliminary action by performing pre-selection steps that identify and isolate aptamers with binding to specific functional groups before the main selection process. This preliminary screening using functional group-specific reagents or analogs prepares the aptamer pool, making the subsequent main selection more efficient and reliable for isolating high-affinity aptamers for sterically hindered targets.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent uses intermediary compounds or analogs that mimic the target molecule's functional groups but with simplified structures that are easier to bind. These intermediaries serve as bridges during the selection process, allowing aptamers to first bind to the simplified analogs and then be selected for binding to the actual sterically hindered target, thereby reducing the apparent complexity of the overall process.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If aptamers are designed to bind sterically hindered functional groups, then affinity for important targets like leucine and voriconazole can be achieved, but steric barriers prevent successful binding

Engineering Contradiction:

Improvebinding affinityVSAvoidsteric hindrance

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies dimensionality change by orienting the aptamer binding approach from a direct head-on collision with the sterically hindered functional group to a side-on or angled approach. By changing the spatial dimension of the binding interaction, the aptamer can access the functional group through gaps or flexible regions, overcoming the steric barrier while maintaining high binding affinity.

Inventive Principle:

Principle #17Another dimension (Dimensionality change)

Solution Approach 2:

The patent utilizes parameter changes by modifying the aptamer's structural parameters such as loop size, stem length, and nucleotide sequence composition to optimize flexibility and binding geometry. By adjusting these parameters, the aptamer can adapt its conformation to accommodate steric hindrance while maintaining effective binding to the functional group, thereby achieving high affinity for challenging targets.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20260015619A1Methods for preparing aptamers for small molecules

Publication Date: 2026.01.15 THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK

AI summary

The present disclosure provides, inter alia, a novel, functional group-guided method for preparing aptamers for small molecules, including those that cannot be obtained by standard protocols. Also provided are aptamers identified and prepared using the method disclosed herein, compositions comprising such aptamers, and methods and kits for treating a condition using the aptamers and/or compositions disclosed herein.