Engineered ACE2 Protein Variants for Nebulized SARS-CoV-2 Therapeutics
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Solution Overview
Problem
Current protein-based biopharmaceuticals lack stability during nebulization, making them unsuitable for treating respiratory infections caused by viruses like SARS-CoV-2 that use ACE2 as a co-receptor, as they degrade during aerosolization, limiting their effectiveness in direct lung application.
Innovation Solution
Development of recombinant human ACE2 protein variants with improved stability and binding affinity to the SARS-CoV-2 spike protein, specifically designed to maintain stability and efficacy during nebulization, administered via a nebulized solution to inhibit viral entry into host cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If protein-based biopharmaceuticals are administered via nebulization, then direct local lung application is achieved, but the protein degrades during aerosolization and loses stability
Solution Approach 1:
The patent applies parameter changes by modifying the protein's physical and chemical properties through engineered mutations. Specifically, the ACE2 protein was engineered with stabilizing mutations (e.g., disulfide bond formation, proline substitutions) that alter its conformational stability parameters, allowing it to withstand the mechanical stress and environmental conditions of nebulization while maintaining its therapeutic function.
Solution Approach 2:
The patent creates a composite therapeutic approach by combining the ACE2 protein with stabilizing engineering modifications. The engineered ACE2 variant incorporates structural elements that enhance stability without compromising binding affinity, effectively creating a composite structure that resists degradation during aerosolization while maintaining biological activity.
2Reliability
If ACE2 protein is engineered for stability during nebulization, then therapeutic efficacy is improved, but protein structure and binding affinity may be compromised
Solution Approach 1:
The patent applies local quality by making targeted mutations at specific locations on the ACE2 protein structure. The stabilizing mutations are introduced in regions that do not interfere with the receptor-binding domain, allowing the protein to have enhanced overall stability while maintaining local binding affinity at the critical interaction sites with the viral spike protein.
Solution Approach 2:
The patent employs partial action by introducing a limited number of strategic mutations rather than comprehensive structural modifications. These selective changes provide sufficient stability enhancement for nebulization without over-engineering the protein structure, thereby preserving natural binding characteristics and avoiding potential loss of affinity.
3Ease of manufacture
If conventional biopharmaceutical delivery is used, then administration is simple, but protein-based therapies lack stability throughout aerosolization
Solution Approach 1:
The patent applies preliminary action by pre-engineering the ACE2 protein with stabilizing modifications before administration. The protein is prepared in advance with structural enhancements that protect it against degradation during nebulization, allowing simple administration via standard nebulizers without requiring complex delivery systems or additional stabilization steps during administration.
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
The recombinant ACE2 protein variants effectively inhibit SARS-CoV-2 replication and show therapeutic potential in treating COVID-19 by maintaining stability and binding affinity throughout aerosolization, demonstrating enhanced bioavailability and therapeutic efficacy.
Implementation Method 1
the recombinant ACE2 protein variants effectively inhibit SARS-CoV-2 replication... by maintaining stability and binding affinity throughout aerosolization
Data Source
AI summary
Disclosed herein are ACE2 recombinant proteins and methods of using such for therapeutic and/or diagnostic purposes. Also provided herein are methods for producing such recombinant proteins.