With a day off and now that we are coming close to the big day (where have I heard that before? See first post this thread dated 01/04/20)
, I thought I would break down a few concepts of our science and where it might lead...... and utilize the paper posted here this week by Teresa Santos-Mendoza.
Most regulars here have become familiar with the smallest of the four structural proteins of corona viruses named E (envelope), which is the target of Bioton's viroporin inhibitor drug, BIT225; 'viroporin' being a protein that permits ion channeling, or the passage of viral particles, and 'ion channel formation appears to be one of the first and most important events in direct viral pathophysiology1.
Ion channeling in its most basic explaination relevant to Covid, is a process where particles can pass out from infected human cells that is part of viral budding which plays no small measure in the increased inflamation caused form the cytokine storm that can lead to fatality.
For those new to BIT, which of course will be many in the very near future, you will be more familiar, knowingly or not, about the structural S protein of the SARS-CoV-2 virus that has caused Covid, as it is the obvious spike formation on the outer surface of the virus that has been pictured in every news article throughout the pandemic. Well, we're not interested in that. It is past its used by date. Ever evolving to evade the vaccination like a Trumpian conspiracist, it has served its purpose resulting in adding to an increased chaotic world. Rather, the highly enigmatic E protein is now what it is all about.
Way back in 1996, even before the company, Biotron was formed, Peter Gage published a paper on HIV that is worth showing the abstract for all its similiarities with the ongoing work on SARS2. What I mean by this is if the untrained eye were to read this, and then was to read one from SARS2 E research, you would be forgiven for thinking that the same mumbo jumbo is describing the same thing. This is because there are distinct relevancies.
Firstly, here are some terms explained
a)
Vpu: the structural ion channeling protein of HIV
b)
endoplasmic reticulum and Golgi membrane: these complex compartments of plant and animal cells (including humans), work in conjunction transforming and releasing proteins and as such are part of the growth cycles of cells. (The E protein of SARS2 infects them).
c)
cation-selective ion channels in phospholipid membranes. This phrase is a regular in SARS2 research do do with E.
In fact, it became an important focal point in the 2004 SARS1 research: Wilson, L, Mckinlay C, Gage P, Ewart,G (2004). SARS coronavirus E protein forms cation-selective ion channels. Virology. 330: 322–331. This is the paper in which the team showed for the first time that E of SARS1 was in fact a viroporin. See first post this thread for further details).
HIV/1996:
Vpu is a small phosphorylated integral membrane protein encoded by the human immunodeficiency virus type 1 genome and found in the endoplasmic reticulum and Golgi membranes of infected cells. It has been linked to roles in virus particle budding and degradation of CD4 in the endoplasmic reticulum. However, the molecular mechanisms employed by Vpu in performance of these functions are unknown. Structural similarities between Vpu and the M2 protein of influenza A virus have raised the question of whether the two proteins are functionally analogous: M2 has been demonstrated to form cation-selective ion channels in phospholipid membranes. In this paper we provide evidence that Vpu, purified after expression in Escherichia coli, also forms ion channels in planar lipid bilayers. The channels are approximately five- to sixfold more permeable to sodium and potassium cations than to chloride or phosphate anions. A bacterial cross-feeding assay was used to demonstrate that Vpu can also form sodium-permeable channels in vivo in the E. coli plasma membrane.
In not wanting to make this too long, let's cut to the chase and focus on pending trial results.
Will the previous mice trial results have the same outcome in the human trial results about to be released? The million dollar question.
Returning to Ms Mendoza's broad review of the literature on drug's targeting E, she refers to the following observation:
The E viroporin acts as a major trigger for the host inflammatory response by activating the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome, thus inducing interleukin (IL)-1β secretion, as well as tumor necrosis factor-alpha (TNFα
and IL-6, and is a determinant of pathogenicity2 .
Say what
?
If we turn to Biotron's latest mice trial results (not the human trials imminently expected, or expected within weeks
), but hopefully these too will show the same, we can read:
These results indicate selective inhibition of E protein ion channel activity by BIT225 and the ability of BIT225 to fully suppress E protein ion channel current 3.
This critically important step, the suppression of ion channling in our little genetically modified ACE2 receptor mice, is what the game is all about. It was first demonstrated back in 2004 in SARS1
in vitro experiments and has gone onto having the same effect in the Vpu of HIV with staggering results for 'curing' HIV (note commas).
Can the ion channeling of E in SARS2 be stopped in Covid infected humans as it is did in HIV infected humans and ACE2 enginered mice with SARS2?
Damn, market open. I knew I shouldn't have slept in from the normal 0330 rise, when I could have easily completed this. Anyway, let's see what the day unfolds.
To be continued
Not long now.
1.
Mukherjee, S.; Bhattacharyya, D.; Bhunia, A. Host-membrane interacting interface of the SARS coronavirus envelope protein: Immense functional potential of C-terminal domain. Biophys. Chem. 2020, 266, 106452. As seen in the paper posted here this week The Envelope (E) Protein of SARS-CoV-2 as a Pharmacological Target,
https://www.mdpi.com/1999-4915/15/4/1000?type=check_update&version=2#B38-viruses-15-01000.
2. Santos-Mendoza, T.
4. The Envelope (E) Protein of SARS-CoVs
3.
Post-infection treatment with the E protein inhibitor BIT225 reduces disease severity and increases survival of K18-hACE2 transgenic mice infected with a lethal dose of SARS-CoV-2
(20min delay)