Trimeric ACE2 Oligomers for Ultra-High Affinity SARS-CoV-2 Neutralization
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Solution Overview
Problem
Current therapeutics for COVID-19, such as recombinant ACE2, have limited efficacy due to moderate binding affinity and potential mutational escape of SARS-CoV-2 variants, necessitating a more effective and broadly neutralizing solution.
Innovation Solution
Engineering trimeric ACE2 (T-ACE2) proteins with high affinity to the SARS-CoV-2 spike protein, utilizing rigid linkers and trimerization motifs like foldon or three-helix bundle, to enhance binding avidity and inhibit viral infection across variants.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If recombinant soluble ACE2 is used to treat COVID-19, then ACE2 function is replenished, but binding affinity to SARS-CoV-2 spike protein is only moderate (KD ~30 nM)
Solution Approach 1:
The patent merges multiple ACE2 monomers into oligomeric structures (dimers, trimers, tetramers, or higher-order oligomers) to increase binding affinity. By combining multiple binding units, the oligomeric ACE2 achieves ultra-high affinity (KD < 1 pM) for the SARS-CoV-2 spike protein, overcoming the moderate affinity limitation of monomeric ACE2 while maintaining the same basic protein structure repeated in a multimeric configuration.
2Reliability
If neutralizing antibodies are developed against SARS-CoV-2, then viral infection is inhibited, but RNA virus mutations can render antibodies ineffective
Solution Approach 1:
The patent designs ACE2 oligomers that serve multiple functions: they act as decoy receptors to block viral entry, function as soluble blockers of the spike-ACE2 interaction, and provide broad-spectrum neutralization against SARS-CoV-2 and related coronaviruses. The oligomeric structure with multiple binding sites enables simultaneous engagement of multiple viral particles or spike proteins, enhancing universal protection against current and future variants.
Solution Approach 2:
The ACE2 oligomers are engineered in advance with ultra-high affinity binding characteristics to preemptively block viral infection before it can occur. The pre-formed oligomeric structures with multiple binding sites are ready to immediately neutralize incoming viral particles, providing proactive protection that is less susceptible to mutational escape compared to antibodies that may require updating as viruses evolve.
3Reliability
If ACE2 concentration is increased to inhibit virus, then viral infection is blocked, but high concentration is required due to moderate binding affinity
Solution Approach 1:
The patent fundamentally changes the binding affinity parameter of ACE2 by transitioning from monomeric to oligomeric structures. This structural parameter change results in ultra-high affinity binding (KD < 1 pM), which is several orders of magnitude stronger than monomeric ACE2. Consequently, much lower concentrations of oligomeric ACE2 are required to achieve effective viral inhibition, improving therapeutic efficacy while reducing the quantity of substance needed.
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
T-ACE2 achieves extremely high binding affinity (KD < 1 pM) and potent neutralization of SARS-CoV-2, its mutants, and related coronaviruses, offering a robust therapeutic approach resistant to mutational escape.
Implementation Method 1
an engineered trimeric ACE2 protein could potentially bind up to three receptor binding domains (RBD) on spike protein to drastically increase binding affinity through avidity effect
Implementation Method 2
Both SARS-CoV-2 and SARS-CoV bind ACE2 for cell entry, SARS-CoV-2 mutants and future related coronavirus will likely bind ACE2 for infection too. Therefore, decoys proteins engineered based on ACE2 could serve as the most broadly neutralizing proteins against these viruses
Data Source
AI summary
Provided are engineered ACE2 oligomers and compositions comprising the oligomers. Also provided are compositions and methods for treating or preventing coronavirus infection and detecting coronavirus.