Proximity Mediated Coupling of Biomolecules via 1,4-Dioxo Recognition
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Solution Overview
Problem
Current biochemistry coupling strategies often rely on highly reactive compounds or pro-reactive systems, which are unstable, toxic, or require external stimuli, leading to issues like product degradation, interference with biological components, and lack of site-specificity and reversibility.
Innovation Solution
A method for covalently binding a first agent to a second agent using a chemo-selective reaction triggered by the non-covalent recognition of a 1,4-dioxo moiety and a nucleophilic moiety, allowing for proximity-induced covalent bond formation without the need for catalysts or external triggers, and achieving site-specific and irreversible coupling under physiological conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If highly reactive compounds are used for coupling, then coupling efficiency is improved, but stability and lifetime of reagents deteriorate due to hydrolysis or oxidation
Solution Approach 1:
The recognition elements are designed to pre-position the reactive groups in close proximity through non-covalent binding, creating a localized high-concentration environment that enables efficient coupling without requiring the bulk reagents to be highly reactive or unstable
Solution Approach 2:
Recognition elements act as intermediaries that bring reactive groups together through specific non-covalent interactions, mediating the coupling process and allowing use of milder, more stable reactive groups that would not couple efficiently without this mediation
2Productivity
If pro-reactive systems activated by triggers are used, then coupling efficiency is improved, but toxicity and damage to biological components worsen
Solution Approach 1:
The system uses self-complementary recognition elements that automatically bind to each other and activate the coupling reaction through their own association, eliminating the need for external triggers such as copper catalysts that are toxic to biological systems
Solution Approach 2:
Recognition elements serve as intermediaries that facilitate the coupling reaction through their binding interaction, replacing toxic external activators with a biocompatible recognition-based activation mechanism
3Adaptability or versatility
If recognition-based coupling without strong bond formation is used, then reversibility is improved, but stability of the coupling worsens due to dissociation
Solution Approach 1:
The coupling system is segmented into two functional parts: recognition elements that provide reversible binding and controllability, and reactive groups that form stable covalent bonds, with the recognition elements acting as a controllable gate for activating the irreversible coupling
Solution Approach 2:
The recognition elements perform preliminary reversible binding to position reactants correctly, and this pre-organization can be controlled or reversed before the final covalent bond formation, providing temporal control over the coupling process
4Manufacturing precision
If site-specific coupling is achieved through specific recognition, then manufacturing precision is improved, but device complexity worsens due to need for specific triggers or conditions
Solution Approach 1:
The system achieves site-specific coupling through self-complementary recognition elements that automatically find and bind to their targets, eliminating the need for complex external triggering systems or specialized equipment to achieve specificity
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 method enables efficient, high-yield, and stable conjugation of biomolecules or surfaces, maintaining bioactivity and stability across a range of conditions, suitable for intracellular applications and low reagent concentrations.
Implementation Method 1
A method for proximity mediated coupling of a first agent to a second agent... chemo-selective reaction triggered by the non-covalent recognition of a 1,4-dioxo moiety and a nucleophilic moiety, allowing for proximity-induced covalent bond formation
Implementation Method 2
non-covalent recognition of two or more elements bringing a 1,4-dioxo moiety and nucleophilic moiety into proximity
Data Source
AI summary
The present invention relates to a method for covalently binding a first agent and a second agent, the first agent comprising a first recognition element, wherein the first recognition element comprises an 1,4-dioxo moiety having a structure of Formula IA, IB or IC, wherein R12 is C1-30alkyl, C2-30alkenyl, C6-15aryl, or C5-15heteroaryl, wherein the C1-30alkyl, C2-30alkenyl, C6-15aryl, or C5-15heteroaryl group are optionally substituted with an C1-6alkyl, C3-6cycloalkyl, halogen, amine, hydroxyl, sulfhydryl, carboxyl, or C1-6alkoxy; and R13, if present, is hydrogen, C1-30alkyl or C2-30alkenyl; the second agent comprising a second recognition element, wherein the second recognition element comprises a nucleophilic moiety selected from a hydrazine moiety, an aminooxy moiety, an aminosulfanyl moiety or a hydroxylamine moiety; wherein: (A) the first recognition element and the second recognition element are capable of non-covalently binding to each other such that the 1,4-dioxo moiety and the nucleophilic moiety are brought in proximity; the method comprising contacting the first agent with the second agent, thereby covalently binding the 1,4-dioxo moiety and the nucleophilic moiety; or (B) the first recognition element and the second recognition element are capable of non-covalently binding to a third recognition element such that the 1,4-dioxo moiety and the nucleophilic moiety are brought in proximity; the method comprising contacting the first agent with the second agent and the third recognition element, thereby covalently binding the 1,4-dioxo moiety and the nucleophilic moiety; wherein the first recognition element is a peptide nucleic acid (PNA), a peptide, a peptidomimetic, an oligonucleotide, an oligonucleotide mimic, or a combination thereof; the second recognition element is a PNA, a peptide, a peptidomimetic, an oligonucleotide, an oligonucleotide mimic, or a combination thereof; and the third recognition element is a nucleic acid, an oligonucleotide, an oligonucleotide mimic, a PNA, a protein, a peptide, a cyclodextrin, a cucurbituril, a cyclophane, or a combination thereof. The invention further provides related products including kits of parts.