Zinc-Depleted ACE2 Polypeptides for Therapeutic Stability
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Solution Overview
Problem
Current ACE2 formulations rely on zinc for stability, but this limits their therapeutic applications and stability, as zinc is not always necessary for ACE2 structure and activity, and other metal ions can replace zinc while maintaining enzymatic activity.
Innovation Solution
Development of ACE2 variants with depleted or no zinc, or substituted with other metal ions such as Co2+, Ni2+, Mn2+, Cu2+, and Fe3+, allowing for the creation of zinc-depleted, zinc-free, and mixed-metal ACE2 polypeptides that can regain activity in the presence of suitable metal ions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If zinc is used to stabilize ACE2 formulations, then structural stability is improved, but therapeutic flexibility and adaptability are limited
Solution Approach 1:
The patent applies parameter changes by systematically varying the metal ion composition in ACE2 formulations. Different metal ions (Zn2+, Co2+, Ni2+, Mn2+, Cu2+, Fe3+) are tested at different concentrations to optimize both stability and therapeutic efficacy. This allows the formulation to be tuned for specific therapeutic applications while maintaining structural integrity.
Solution Approach 2:
The patent demonstrates that ACE2 can function with multiple different metal ions, not just zinc. This multi-functionality principle is applied by showing that various metal ions can substitute for zinc while maintaining catalytic activity, thereby expanding the therapeutic versatility of ACE2 formulations for different disease indications.
2Reliability
If zinc is required for ACE2 activity, then enzymatic function is maintained, but formulation complexity and manufacturing constraints increase
Solution Approach 1:
The patent applies the extraction principle by removing the strict requirement for zinc from ACE2 formulations. By demonstrating that other metal ions can substitute for zinc, the patent extracts the essential function (metal ion coordination) from the specific constraint (zinc requirement), thereby simplifying formulation complexity while maintaining enzymatic reliability.
3Reliability
If zinc is complexed in the active centre, then catalytic activity is maintained, but loss of enzyme-bound zinc occurs during storage
Solution Approach 1:
The patent applies beforehand cushioning by pre-stabilizing the metal ion coordination in ACE2 through optimized formulation conditions. By establishing stable metal ion binding through appropriate buffer composition and pH control before storage, the patent prevents loss of enzyme-bound metal ions during storage and transport, thereby maintaining catalytic activity without requiring excess zinc supplementation.
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
These variants offer enhanced stability and flexibility in therapeutic applications, allowing for fine-tuning of ACE2 activity and bioavailability, and can maintain enzymatic activity in human plasma without additional zinc, providing a broader range of treatment options for diseases like hypertension and fibrosis.
Implementation Method 1
ACE2 is described as a zinc containing metalloprotease, a so-called zinc-protease. The current fully active formulations for clinical use contain an equimolar zinc/protein ratio. Zinc is thereby complexed in the active centre of the enzyme.
Implementation Method 2
ACE2 variants with depleted or no zinc, or substituted with other metal ions such as Co2+, Ni2+, Mn2+, Cu2+, and Fe3+, allowing for the creation of zinc-depleted, zinc-free, and mixed-metal ACE2 polypeptides that can regain activity in the presence of suitable metal ions.
Data Source
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AI summary
The present invention relates to modified angiotensin converting enzyme 2 (ACE2) polypeptides and pharmaceutical and analytical uses thereof. In particular, the present invention relates to Zn2+ depleted-, Zn2+ free-, mixed metal- and metal ion substituted-ACE2 as well as methods for the manufacture of these variants and uses thereof, such as therapeutic and analytic uses of these ACE2 variants.