Modified ACE2 Polypeptides for SARS-CoV-2 Binding
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a need for effective therapies to treat SARS-CoV-2 infection as no vaccine or approved drugs are currently available to prevent or treat COVID-19, and existing ACE2 proteins do not efficiently bind to the S protein of SARS-CoV-2, limiting their therapeutic potential.
Innovation Solution
Modified human ACE2 polypeptides with enhanced folding and increased binding affinity to the S protein of SARS-CoV-2 are developed, including specific amino acid substitutions and fusion proteins with heterologous polypeptides like Fc proteins for improved stability and diagnostic/detection capabilities, which can be used for prophylaxis, treatment, and detection of COVID-19.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type ACE2 protein is used, then it maintains natural structure and function, but it does not bind efficiently to SARS-CoV-2 S protein, limiting therapeutic potential
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions (N330Y, L359F, L386A) into the ACE2 protein sequence. These substitutions modify the binding interface parameters to increase affinity for SARS-CoV-2 S protein while maintaining the overall protein fold and function. The mutations are designed to optimize hydrophobic interactions and structural complementarity at the binding interface.
Solution Approach 2:
The patent creates composite protein structures by fusing ACE2 with heterologous polypeptides such as Fc regions of antibodies or albumin. This composite approach enhances serum stability, extends half-life, and improves pharmacokinetic properties while retaining the viral binding capability of ACE2. The fusion proteins combine the receptor-binding function of ACE2 with the stability and longevity characteristics of the fused partner.
2Reliability
If ACE2 protein is modified to increase binding affinity, then therapeutic efficacy improves, but protein stability and folding may be compromised
Solution Approach 1:
The patent carefully selects amino acid substitutions that modify binding interface parameters without disrupting the core structural parameters of ACE2. The N330Y, L359F, and L386A mutations are positioned at the binding interface rather than in structurally critical regions, allowing enhanced affinity while preserving overall protein stability and correct folding.
Solution Approach 2:
The patent uses computational modeling and structural biology as intermediaries to predict and validate the effects of mutations before experimental implementation. Molecular dynamics simulations and free energy calculations serve as intermediaries to assess whether proposed mutations will maintain protein stability while improving binding affinity, reducing the risk of destabilizing the protein structure.
3Duration of action of stationary object
If fusion proteins with heterologous polypeptides are created, then serum stability and diagnostic capabilities improve, but device complexity increases
Solution Approach 1:
The patent creates multi-functional fusion proteins where ACE2 provides viral binding capability, Fc regions provide extended half-life and effector functions, or albumin provides stability and long circulation. Each fusion partner contributes specific functions that enhance the overall therapeutic profile, making the single molecule perform multiple roles that would otherwise require separate components.
Solution Approach 2:
The patent utilizes the well-characterized and extensively studied Fc region structure from natural antibodies as a template for fusion design. By copying the proven stability and pharmacokinetic properties of the Fc domain, the patent achieves extended serum half-life without needing to de novo design a stable protein scaffold, leveraging existing biological knowledge to simplify the design process.
Data Source
AI summary
The modified polypeptides include at least one amino acid substitution that allows the polypeptide to bind better to the S surface glycoprotein of coronaviruses that use ACE2 as a cell entry receptor, either through direct increases in affinity or through improved folding and expression of ACE2. Use of the modified ACE2 polypeptides for inhibiting CoV entry, replication and/or spread, for pre-exposure and post-exposure CoV prophylaxis, and for treating a CoV infection (e.g. COVTD-19), is also described.