Engineered Ligand Nanobody GPCR Affinity

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Solution Overview

Problem

Current ligands for G-protein coupled receptors (GPCRs) often exhibit sub-optimal affinity and specificity, leading to promiscuous binding and reduced potency, which limits their effectiveness in modulating receptor activity.

Innovation Solution

Engineered ligands are created by conjugating a sub-optimal ligand to a targeting molecule, such as a nanobody, which binds to a second site on the receptor, enhancing affinity, potency, and specificity by forming a complex with the GPCR.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If a sub-optimal ligand is used for a GPCR, then the ligand structure is simple, but the binding affinity and potency are insufficient

Engineering Contradiction:

Improvebinding affinityVSAvoidligand structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent combines a sub-optimal ligand with a targeting molecule (such as a nanobody) to create an engineered ligand. The sub-optimal ligand binds to the first binding site on the GPCR while the targeting molecule binds to a second binding site, merging two binding interactions to achieve high overall affinity and potency without requiring the original ligand to be complex

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The engineered ligand is constructed as a composite structure comprising a sub-optimal ligand component and a targeting molecule component. This composite approach allows each component to contribute its specific binding properties, achieving superior performance compared to either component alone

Inventive Principle:

Principle #40Composite materials

2Reliability

If a natural ligand is used for a GPCR, then the ligand is simple, but the specificity is low leading to promiscuous binding

Engineering Contradiction:

ImprovespecificityVSAvoidligand structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent merges a sub-optimal ligand that provides baseline specificity with a targeting molecule that enhances receptor selectivity. The targeting molecule is designed to bind to a second binding site that is unique to the target GPCR, thereby improving overall specificity and reducing promiscuous binding to off-target receptors

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The engineered ligand applies local quality by having different components target different binding sites with different specificity requirements. The sub-optimal ligand binds to one site while the targeting molecule binds to another site with high specificity, creating a bimodal binding strategy that enhances overall receptor selectivity

Inventive Principle:

Principle #3Local quality

3Reliability

If a sub-optimal ligand is used for a GPCR, then the ligand is simple, but the potency in modulating receptor activity is reduced

Engineering Contradiction:

ImprovepotencyVSAvoidligand structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent combines a sub-optimal ligand with a targeting molecule to create an engineered ligand where the sub-optimal ligand binds to the first binding site on the GPCR and the targeting molecule binds to a second binding site. This dual-binding mechanism synergistically enhances the potency of the ligand in modulating receptor activity, achieving greater effect than either component alone

Inventive Principle:

Principle #5Merging (Combining)

Data Source

PatentUS11878063B2Engineered ligands and uses thereof

Publication Date: 2024.01.23 CHILDRENS MEDICAL CENT CORP

AI summary

Described herein are engineered ligand that binds a cell surface receptor (e.g., GPCR), with improved affinity, potency, and specificity. By conjugating a sub-optimal ligand for a cell surface receptor (e.g., GPCR) to a targeting molecule that binds an epitope (natural or exogenous epitope) in the extracellular portion of the cell surface receptor (e.g., GPCR), the affinity, potency, and/or specificity of the sub-optimal ligand is enhanced.