Endosidin 2 Composition for Blocking ACE2 Surface Translocation
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Solution Overview
Problem
The mechanism by which SARS-CoV-2 infects human peripheral blood cells, particularly monocytes and macrophages, is unclear, as these cells lack mRNA expression of the angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease type 2 (TMPRSS2) receptors, raising concerns about viral spread to other organs.
Innovation Solution
The use of endosomal trafficking inhibitor endosidin 2 (ES2) to block the translocation of ACE2 to the cell surface, thereby reducing the susceptibility of immune cells to SARS-CoV-2 infection by inhibiting exocytosis and endocytosis recycling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If ACE2 translocates to the cell surface through endosomal trafficking, then SARS-CoV-2 infection susceptibility increases, but blocking this translocation prevents viral entry
Solution Approach 1:
The patent uses endosidin 2 (ES2) as an intermediary substance that blocks the endosomal trafficking pathway. ES2 inhibits the translocation of ACE2 from the cytoplasm to the cell surface by interfering with endosome function, thereby preventing SARS-CoV-2 entry without directly interacting with the virus or ACE2 itself
Solution Approach 2:
The patent replaces the natural endosomal trafficking mechanism with an inhibited state. By using ES2 to block endosome function, the cell cannot utilize its normal endocytic pathway for ACE2 translocation, effectively substituting the mechanical process of vesicular transport with a blocked/inactive state
2Reliability
If exocytosis is inhibited to reduce ACE2 surface expression, then viral infection is prevented, but normal cellular secretion functions are impaired
Solution Approach 1:
The patent applies local quality by targeting specifically the endosomal trafficking pathway for ACE2 translocation while attempting to preserve other cellular secretion functions. ES2 selectively interferes with the endosome recycling pathway that is critical for ACE2 surface expression, while normal exocytosis of other proteins may remain functional
Solution Approach 2:
The patent changes the functional state of the endosomal trafficking system by introducing ES2, which alters the kinetics and regulation of ACE2 translocation. This parameter change in endosome function specifically impacts viral entry pathways while potentially maintaining other cellular processes
3Reliability
If endosomal trafficking is blocked to prevent ACE2 translocation, then immune cell infection is reduced, but cellular responses to stimulation are impaired
Solution Approach 1:
The patent employs endosidin 2 as a mediator that specifically targets the endosomal trafficking step in ACE2 translocation. By blocking this intermediate step, the cell cannot produce surface ACE2 in response to TLR stimulation, thereby preventing viral entry while the stimulation itself remains functional
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
Prevents SARS-CoV-2 infection by inhibiting ACE2-mediated entry into immune cells, potentially reducing systemic viral spread and severe inflammation.
Implementation Method 1
a composition comprising ES2, or a pharmaceutically acceptable salt thereof, for use in inhibiting exocytosis in an immune cell. Inhibiting exocytosis in an immune cell can reduce ACE2 translocation to the cell membrane of an immune cell
Implementation Method 2
a composition comprising ES2, or a pharmaceutically acceptable salt thereof, for use in inhibiting endocytosis recycling. Inhibiting endocytosis recycling in an immune cell can also reduce ACE2 translocation to the cell membrane of the immune cell
Implementation Method 3
In ex vivo TLR4/7/8 stimulation, cytoplasmic ACE2 quickly translocated to the monocyte cell surface independently of ACE2 transcription
Data Source
AI summary
A composition comprising ES2 prevents ACE2 translocation to the cell surface and susceptibility to SARS-CoV-2 infection. Treating a subject with a composition comprising the compound ES2 may reduce the risk of severe COVID-19. The prognosis of COVID-19 in a subject can be predicted by measuring ACE2 and inflammatory and immunosuppressive phenotypes on isolated peripheral blood mononuclear cells by flow cytometry.