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How many mechanisms do you need? Ivermectin works against Covid in 20 ways

Some claim that we don’t know how ivermectin works, but oh boy we do

Not only do we know how ivermectin protects us, we know many pathways in detail. Ivermectin is useful at every stage of the disease. In the early stages, it reduces the odds of people getting infected, stops the virus multiplying, which reduces the viral load and the spread of the virus to your friends and strangers on the bus.  It helps our cells warn neighboring cells to get ready for a viral attack. It stops the virus getting through the outside wall of our cells, and also stops parts of the virus getting into the headquarters of our cells, the nucleus, where our DNA is.

Ivermectin is also a zinc ionophone which helps zinc cross into cells so zinc can do the good things zinc does…

As the virus tried to assemble itself inside our cells one of the processing tasks involves chopping long proteins into shorter parts. There are many enzymes involved but ivermectin binds to one key one called a Chymotrypsin-like-protease. Ivermectin also conveniently binds to two of the virus proteins as well (called Mpro and PLpro). Basically, ivermectin is the glue no assembly line wants.

In the late stages, ivermectin is an anti-inflammatory drug that reduces the cytokine storm in something like six different ways.

Ivermectin is not just “gum in the works” it’s a kind of Swiss-knife-Velcro-tool — the most sticky, most useful, lock-and-key anti-viral.

With so many  mechanisms of action, it’s difficult for the virus to outsmart ivermectin and mutate around multiple blocks at once. We needed a three-drug-antiviral-cocktail to beat AIDS,  but in terms of resistant mutants arising, Ivermectin is an anti-viral cocktail all by itself. (Obviously used as part of a full medical program.)

Two researchers in Italy, Asiya Kamber Zaidi and Puya Dehgani-Mobaraki, published a paper detailing the 20 different levels of action. It’s quite the marvel, and it came out in May. (Don’t our Chief Health Officers read these papers?)

Ivermectin is the new penicillin

Penecillin changed the world. Imagine if they had banned it?

Click to enlarge:

Zaidi, Mechanisms of Action, Ivermectin, SARS-2, Covid-19

Zaidi, Mechanisms of Action, Ivermectin, SARS-2, Covid-19 (See below for the caption with all the acronyms listed in detail.)

 

As the researchers say, “The probability that an ineffective treatment generated results as positive for the 55 studies to date is estimated to be 1 in 23 trillion (p = 0.000000000000043)”.

Three ways to stop that virus getting in:

Ivermectin binds to the spike (at leucine 91), but it also binds to our ACE2 receptors as well  (at histidine 378). It clogs up the lock-and-key from both ends, and when compared to Remdesivir and hydroxychloroquine, ivermectin bound more strongly to the spike than any of them.

“The free binding energy of the spike protein (open) was higher in Ivermectin (−398.536 kJ/mol) than remdesivir (−232.973 kJ/mol).” (Ewaes 2021)

In this case “higher” means more negative. The higher it is, the more strongly something binds. Negative binding energies mean that binding is spontaneous, and doesn’t need an external energy source.

Ivermectin binds SARS Cov-2 spike. Diagram. Chemistry. Molecule.

From Lehrer et al

 

Ivermectin also binds to TMPRSS2 — it’s not a celebrity molecule like ACE2 — perhaps because someone didn’t think through the PR campaign and call it “Empress2” or something pronounceable  — but it is just as important apparently as ACE2. It seems SARS-2 can’t get into cells which have ACE2 on the surface but don’t also have the TMPRSS2 enzyme there as well (Parmar 2021). Think of TMPRSS2 as a pair of secateurs wandering around the cell surface that need to prune the Covid spike before it can use ACE2 to get into a cell. TMPRSS2 is the not so catchy name for Transmembrane serine protease 2.

Ivermectin also had the highest binding affinity for TMPRSS2. By binding so well to all three — the spike, the ACE2 receptor and the TMPRSS2 secateurs that prune or prime the spike, ivermectin makes it much harder for the virus to get inside a cell.

Protecting the cell nucleus

Once inside a cell, the virus gains access to most resources and tools it needs to produce “baby viruses”, but there’s much more strategy to this war than just a hijacking. Some viral proteins will be sent like trojan gifts to get inside the cell nucleus —  which is effectively the command centre. To get through the locked “gates” into the nucleus, these proteins must get tagged by two labels called importin-α and importin-β   — they mark “the cargo” as something headed for the nucleus. But ivermectin also binds to importin-α, competing with it for spots, and again foiling the virus, clogging up the system and making it hard for SARS2 to send these proteins through the gates.

This is especially important because the nucleus will send out warning signals to other cells — and the viral proteins aim to stop that alarm system being triggered.

Ivermectin helps cells sound the alarm

One of the first cytokines or messengers that a cell-under-siege sends out is called interferon (these names have a kind of Star Trek feeling, don’t they?). Interferon works like an air raid siren. When it reaches other cells, it triggers an array of downstream effects. Cells ramp up their wartime defenses, like for example, making particular enzymes and immune markers they’ll need. But they also slow down the factories and machinery within them that make proteins. These are the same factories the virus wants to hijack and run at high speed to produce its own weapons and baby viruses. In effect, cells are sabotaging their own infrastructure temporarily, to buy time. Some white blood cells called natural killer cells, also respond to interferon. It’s a big deal.

This is such an important advantage for the virus there are at least three SARS proteins that antagonize or work against the interferon signaling system. If the virus can keep infected cells from releasing interferon, it can multiply unhindered for longer. This is all occurring during the early asymptomatic phase. Indeed, the interferon cascade will cause many of the symptoms that tell us we’re coming down with something — like the fever, the aches, and the “flu-like malaise”. Viruses that can slow this process can stop us feeling sick and keep us on our feet — unwittingly shedding baby viruses to infect the guys in the office or the kids at school.

The delay in interferon production not only helps the virus multiply and spread, but also increases the proinflammatory cytokines that cause so much trouble later.

Ivermectin is a multipronged anti-inflammatory

TLR4, toll like receptor 4

TLR4, Toll like receptor 4,   by  David Goodsell

The Covid virus isn’t the only virus that attacks our interferon signally system, though it is a real hallmark of SARS-2, and ultimately the virus wreaks havoc with cytokines on many levels.  Luckily ivermectin also works on several parts of the immune network and mostly the effect appears to be to slow down the key amplifiers that tend to run off the rails in bad Covid infection. Sorry, immunology is acroynm-hell, so bear with me, you’ll get some idea of just how many pathways are affected. For starters, ivermectin slows down the Toll- like-Receptor-4 (TLR4)– these are ancient guards that have been around for a long time. They watch out for signs of spare parts of both bacteria and viruses and even just chemicals that are bad, and have a “pivotal role as an amplifier”. We need our TLR4, we just don’t want it to get “stuck on”.

Strap yourself in, there is so much more. Ivermectin also blocks the NF-κB pathway (Nuclear Factor-κB). It suppresses the Akt/mTOR signalling, which inhibits PAK1 which reduces STAT3 and IL-6.  STAT3 induces C-reactive protein (or CRP), so less STAT3 means less CRP. These are big names in the world of immunology. Your doctor measures your CRP as a sign of inflammation. People interested in living longer talk about the mTOR system  — it’s a is a kind of master controller for the whole cell cycle. Meanwhile IL-6, or interleukin 6 is another messenger that goes “inflammatory” in diseases like diabetes, depression, Alzheimers, and atherosclerosis.  Obviously, it’s better to face Covid without having “raised inflammatory markers” at the start.

Stopping at least one kind of coagulation

Because ivermectin binds to the virus spike at the right point it stops the virus sticking to the CD147 receptors of red blood cells. Each virus has about 100 spikes, so we can imagine how a swarm of viruses would work like a kind of malevolent velcro to agglomerate red blood cells into blobs that can’t pass through blood vessels. There are lot of other ways blood can clot, but ivermectin smooths this form.

The safety tests have already been done

If ivermectin was a new drug discovery, and we read this paper, we might be spooked that ivermectin is so intimately and intricately involved with our core biochemistry. Wise researchers might warn that it may have significant unpredictable side effects and we should research it carefully — but most of those tests have already been done. Thanks to 30 years of mass human use with 3.8 billion doses we are aware there are only a few situations where ivermectin is dangerous, and doctors know all about that. People can still do damage through overdosing. Doses always matter. Ivermectin can bind to our GABA receptors if it can get across the blood brain barrier. In normal healthy people the blood-brain-barrier is intact and and the drug is actively excluded. Doctors should be free to prescribe this “off label”.

No leaky vaccine should be used without an antiviral back up.

Currently, infected people are generating nastier variants because the vaccines are leaky — vaccines reduce the severity (at least for some months) but they don’t stop people shedding and transmitting the virus. We risk generating more deadly forms of Covid — just as we have unwittingly generated more deadly forms of Marek’s disease in domestic chickens by giving them leaky vaccines for the last 50 years.

All of this could stop, and all of this was known months ago.

*Immunology is alphabet soup. If I have vastly oversimplified, I trust commenters will correct me.

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UPDATE: Thanks to Red Edwards– this article has “been retracted”, but is still downloadable here.

The editors objections:

The Editor-in-Chief has retracted this article. Following publication, concerns were raised regarding the methodology and the conclusions of this review article. Postpublication review confirmed that while the review article appropriately describes the mechanism of action of ivermectin, the cited sources do not appear to show that there is clear clinical evidence of the effect of ivermectin for the treatment of SARS-CoV-2. The Editor-in-Chief therefore no longer has confidence in the reliability of this review article. None of the authors agree to this retraction. The online version of this article contains the full text of the retracted article as Supplementary Information.

50 Studies are never enough. The article cites: real-time meta analysis of 52 studies listed at Ivmmeta.com. 2021 [on 2 May 2021]. Available from: https://ivmmeta.com/.

There are 65 studies there now.

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Fig. 1 Caption

A schematic of the key cellular and biomolecular interactions between Ivermectin, host cell, and SARS-CoV-2 in COVID-19 pathogenesis and prevention of complications.

Ivermectin; IVM (red block) inhibits and disrupts binding of the SARS-CoV-2 S protein at the ACE-2 receptors (green). The green dotted lines depict activation pathways and the red dotted lines depict the inhibition pathways. The TLR-4 receptors are directly activated by SARS-CoV-2 and also by LPS mediated activation (seen during ICU settings) causing activation of NF-Kb pathway and MAP3 Kinases leading to increased intranuclear gene expression for proinflammatory cytokines and chemokines (responsible for cytokine storm) and NO release (responsible for blood vessel dilatation, fluid leak, low blood pressure, ARDS and sepsis). The NF-Kb and STAT-3 pathway activation is central to the pathogenesis and sequelae of COVID-19. STAT-3 physically binds to PAK-1 and increases IL-6 transcription. The annexin A2 at the cell surface converts plasminogen; PLG to plasmin under the presence of t-PA. Plasmin triggers activation and nuclear translocation of STAT-3. An upregulation of STAT-3 stimulates hyaluronan synthase-2 in the lung cells causing hyaluronan deposition leading to diffuse alveolar damage and hypoxia. STAT-3 also directly activates TGF-beta initiating pulmonary fibrosis; a typical characteristic of SARS-COV-2 lung pathology. The damaged type 2 cells express PAI-1 and an already hypoxic state also causes an upregulation of PAI (through Hypoxic inducible factor-1) along with direct stimulation by STAT-3. Simultaneous STAT-3 and PAI-1 activation inhibits t-PA and urokinase-type plasminogen activator leading to thrombi formation. Also, the SARS-CoV-2 spike protein binds to the CD147 on red blood cells and causes clumping. IVM in turn, binds to SARS-CoV-2 Spike protein and hence prevents clumping. T cell lymphopenia in COVID-19 can also be attributed to the direct activation of PD-L1 receptors on endothelial cells by STAT-3. IVM directly inhibits the NF-kb pathway, STAT-3, and indirectly inhibits PAK-1 by increasing its ubiquitin-mediated degradation. The natural antiviral response of a cell is through interferon regulatory genes and viral RNA mediated activation of TLR-3 and TLR7/8- Myd88 activation of transcription of interferon-regulator (IRF) family. For a virus to establish an infection, this antiviral response needs to be inhibited by blocking interferon production. The proteins such as importin and KPNA mediate nuclear transport of viral protein and subsequent IFN signaling. The SARS-CoV-2 proteins (ORF-3a, NSP-1, and ORF-6) directly block IFN signaling causing the surrounding cells to become unsuspecting victims of the infection. IVM inhibits both importin a-b (green) as well as the KPNA-1 receptors (brown) causing natural antiviral IFN release. IVM also inhibits viral RdrP, responsible for viral replication. IVM Ivermectin, ACE-2 angiotensin-converting-enzyme 2, LPS Lipopolysaccharide, TLR Toll-like receptor, t-PA tissue-like plasminogen activator, PLG Plasminogen, IMPab Importin alpha-beta, Rdrp RNA dependant RNA polymerase, KPNA-1 Karyopherin Subunit Alpha 1, NF-kB nuclear factor kappa-light-chain-enhancer of activated B cells, Map3Kinases Mitogen-activated Kinases, PAK-1 P21 Activated Kinase 1, STAT-3 Signal transducer and activator of transcription 3, PAI-1 Plasminogen activator inhibitor-1, HIF-1 Hypoxia-Inducible Factor

REFERENCES

Asiya Kamber Zaidi and Puya Dehgani-Mobaraki (2021) The mechanisms of action of Ivermectin against SARS-CoV-2: An evidence-based clinical review article, 2021 Jun 15 : 1–13. doi: 10.1038/s41429-021-00430-5 [Epub ahead of print]

Eweas AF, Alhossary AA, Abdel-Moneim AS. Molecular docking reveals Ivermectin and Remdesivir as potential repurposed drugs against SARS-CoV-2. Front Microbiol. 2021;11:592908. doi: 10.3389/fmicb.2020.592908. [PMC free article] [PubMed] [CrossRef] []

Lehrer S, Rheinstein PH. Ivermectin Docks to the SARS-CoV-2 Spike Receptor-binding Domain Attached to ACE2. Vivo. 2020;34:3023–6. doi: 10.21873/invivo.12134. [PMC free article] [PubMed] [CrossRef] []

Parmar (2021) TMPRSS2: An Equally Important Protease as ACE2 in the Pathogenicity of SARS-CoV-2 Infection, 2021 Nov; 96(11): 2748–2752.  doi: 10.1016/j.mayocp.2021.07.005

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