Drug-Controlled Polypeptide Systems for Precise Recombinase Control

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Solution Overview

Problem

Existing biological sensors, switches, and logical circuits for controlling cellular signaling and gene expression face issues such as 'leaky' behavior and toxicity, making them unsuitable for systemic administration or clinical use.

Innovation Solution

Development of polypeptide systems comprising a drug-controlled peptide docking domain, a cognate docking domain-binding peptide, and a recombinase with decreased cooperativity mutations, allowing for precise control of recombinase activity and association of activity-complementing domains.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing biological sensors, switches, and logical circuits are used to control cellular signaling and gene expression, then control of cellular therapies is achieved, but leaky behavior occurs and toxicity is induced

Engineering Contradiction:

Improvecontrol precisionVSAvoidtoxicity

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The invention divides the control system into separate functional modules: a drug-controlled peptide docking domain that responds to external drug signals, a cognate docking domain-binding peptide for specific recognition, and a recombinase with decreased cooperativity mutations for controlled DNA recombination. This segmentation allows independent optimization of each component to reduce leakiness and toxicity while maintaining control precision.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention modifies the recombinase cooperativity parameter through specific mutations to decrease its tendency for unwanted activation. By changing the biochemical parameters of the recombinase enzyme, the system achieves tighter control with reduced background activity, thereby improving reliability without increasing toxicity.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If existing biological sensors, switches, and logical circuits are used, then cellular signaling control is achieved, but leaky behavior occurs

Engineering Contradiction:

Improvecontrol precisionVSAvoidactivation threshold control

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The invention introduces local quality differences through the drug-controlled peptide docking domain, which has specific binding characteristics that differ from the cognate docking domain-binding peptide. This local differentiation in binding affinity and specificity allows precise control of activation thresholds, reducing leaky behavior while maintaining reliable signaling control.

Inventive Principle:

Principle #3Local quality

3Adaptability or versatility

If existing control systems are used, then gene expression control is achieved, but the systems are not practicable for systemic administration

Engineering Contradiction:

Improvesystemic administration capabilityVSAvoidtoxicity

Core Design Contradiction:

Adaptability or versatilityVSObject-affected harmful factors

Solution Approach 1:

The invention introduces a drug-controlled peptide docking domain as an intermediary that mediates between the external drug signal and the internal recombinase activation. This intermediary layer allows systemic administration of drugs to control cellular therapies without direct contact between toxic recombination components and systemic circulation, thereby improving adaptability while reducing harmful effects.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20230241026A1Novel drug-controlled systems and uses thereof

Publication Date: 2023.08.03 TRUSTEES OF BOSTON UNIV

AI summary

The technology described herein is directed to polypeptide systems using drug-controlled peptide docking domains and cognate docking domain-binding peptides and their use to control cellular signaling, activity, and/or gene expression.