Mutated ACE2 Fusion Polypeptides for Coronavirus Spike Binding
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Solution Overview
Problem
Existing neutralizing antibodies against viruses like SARS-CoV-1 and SARS-CoV-2 are often too specific and do not cross-react with viral variants, and native ACE2 has low affinity for coronavirus spike proteins, limiting its therapeutic potential.
Innovation Solution
Development of recombinant/fusion polypeptides comprising mutated ACE2 proteins with immunoglobulin fragments, such as human IgG Fc fragments, and specific mutations at positions like 27, 31, 34, and 42 to enhance binding affinity and neutralizing potency against SARS-CoV-1 and SARS-CoV-2.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If native ACE2 is used as a therapeutic, then it can bind to coronavirus spike proteins, but its binding affinity is too low to be effective
Solution Approach 1:
The patent applies parameter changes by introducing specific point mutations (e.g., T27Y, K31H, H34A, H34V) at critical amino acid positions in the ACE2 protein. These mutations alter the binding interface parameters to enhance affinity for coronavirus spike proteins while maintaining or improving neutralizing activity against multiple variants.
Solution Approach 2:
The patent applies local quality by making targeted changes at specific locations in the ACE2 protein structure. The mutations are localized to the receptor binding domain interface where interaction with the spike protein occurs, rather than altering the entire protein. This localized modification optimizes binding at the critical interface while preserving other functional regions.
2Reliability
If neutralizing antibodies are used against a particular virus, then they can block infection effectively, but they do not cross-react with viral variants
Solution Approach 1:
The patent applies universality by designing ACE2 mutants that can bind to and neutralize multiple coronavirus variants simultaneously. The mutated ACE2 protein serves as a universal therapeutic agent effective against SARS-CoV-1, SARS-CoV-2, and various variants (Alpha, Beta, Gamma, Delta, Omicron), rather than being specific to a single viral strain.
Solution Approach 2:
The patent applies copying by using the ACE2 protein as a functional copy of the natural receptor. The mutated ACE2 replicates the receptor's binding capability but with enhanced affinity and broader specificity, effectively copying the viral interaction mechanism while improving performance against multiple variants.
3Adaptability or versatility
If ACE2 is used as a decoy receptor, then it can compete with host cell ACE2 for viral binding, but native ACE2 has insufficient affinity to block infection
Solution Approach 1:
The patent applies parameter changes by modifying the binding interface parameters of ACE2 through point mutations. These changes increase the affinity of the decoy receptor for the spike protein, enabling it to outcompete the host cell's native ACE2 for viral binding and effectively block infection.
Data Source
AI summary
The invention relates to recombinant mutated angiotensin converting enzyme 2 (ACE2) comprising one or more amino acid substitutions at amino acid positions T27, F28, K31, H34, Y41 and Q42 which have improved binding affinity to SARS-CoV-1 and/or SARS-CoV-2. It also relates to combinatorial mutant ACE2 comprising T27Y/K31 H/H34A, T27YZ K31 H/H134V and T27Y/K31 Y/H134V and the use of said mutant ACE2 for treating and preventing coronavirus infection.