How does Ivermectin actually Combat COVID-19?

IN COVID-19 Protection

This is a work-in-progress. (Living Document as I research). I will delete this message when finished.

Started: May 24, 2021
Last Updated: Jul 23, 2021

I already have posts which contain research and videos that share that Ivermectin is effective against COVID-19, but today I really wanted to understand “how” it works. Why does it work? For a non-medical professional, reading through the research really hurts the brain – it’s a different language, and whilst it’s good to know ‘that’ it works, I wanted to know “how or why” it works.

So today I have all the research articles open on one screen and I am looking up “explainer videos” for the terms I don’t understand on the other, and this blog post contains my notes as I attempt to put the pieces of the puzzle together. With the help of various explainer-videos in combination with the scientific-stuff in the research papers, hopefully I can grasp a better understanding in my own mind how it’s effective in combatting COVID-19, which may or may not be useful to anyone that comes across this post (because there’s no guarantee I’ve understood it correctly being that I’m not in that field), but I’m posting my notes here for my own reference.

Ivermectin helps in all stages of the disease…

  1. as a preventative ((Prophylactic role of ivermectin in SARS-CoV-2 infection among healthcare workers)) ((USEFULNESS of Topic Ivermectin and Carrageenan to Prevent Contagion of Covid 19 (IVERCAR) )) ((Study of the efficacy and safety of topical ivermectin+ iota-carrageenan in the prophylaxis against COVID-19 in health personnel))
  2. a treatment ((Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019)) ((Ivermectin Treatment May Improve the Prognosis of Patients With COVID-19)) ((The use of compassionate Ivermectin in the management of symptomatic outpatients and hospitalized patients with clinical diagnosis of COVID-19)) ((Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019)) ((Ivermectin may be a clinically useful anti-inflammatory agent for late-stage COVID-19))
  3. on long-covid (depending on what caused the long-covid) ((Ivermectin In Long-Covid Patients)) ((Post-Acute Or Prolonged Covid-19: Ivermectin Treatment For Patients With Persistent Symptoms Or Post-Acute))
  4. and continues to work as a preventative/treatment on the new Variants ((Ivermectin Works For COVID-19 – LATEST STUDIES 20 Oct 2020)) ((Database of all ivermectin COVID-19 studies – Kept Up-to-Date)) ((Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19)) ((Current IVM-COVID-19 trials – Up-to-Date))

105 studies of Ivermectin in COVID-19 (in 32 countries) have been registered. Of which, 24 have been completed and published. And the results showed that “Ivermectin is almighty for prophylaxis, for treatment of early and late stage, and also for long COVID (or) post-acute sequelae (of SARS-CoV-2)”.

Morimasa Yagisawa – Yagisawa, 79, is among four authors of an article titled, “Global trends in clinical studies of ivermectin in COVID-19” ((Global trends in clinical studies of ivermectin in COVID-19)) that was published in March in The Japanese Journal of Antibiotics. His fellow author is Satoshi Omura, who, along with William Campbell, was awarded the 2015 Nobel Prize in Physiology or Medicine for discovering the drug, avermectin, a derivative of which is the ivermectin.
Screenshot from Prof. Morimasa Yagisawa’s presentation during a virtual interview on May 6, 2021. ((WHO, state regulators asked to consider positive results of ivermectin trials on COVID-19)) ((Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19))

Although Ivermectin is well-known as an antiparasitic drug, additional uses for Ivermectin and other Avermectin derivatives continue to be found. As an antiparasitic, it attaches to the worm’s Glutamate receptor and binds with the chloride channels of the worm’s muscles/nerves and opens them which causes chloride to enter the cell of the worm, which polarizes the cell and makes it more difficult to function. How it works “to combat SARS-CoV-2”, is what I’m attempting to understand today:

Ivermectin COVID-19 Mechanism Nutshell:

  • IVM hinders the binding of the SARS-COV-2 spike protein with the ACE2 receptor on our cells
  • IVM disrupts the importin (IMP) α/β receptor which is responsible for transmitting viral proteins into the host cell nucleus
  • IVM disrupts the RdRp enzyme of the virus reducing the virus’s replication
  • IVM disrupts the viral main proteinase – the 3-Chymotrypsin Like Protease(3CLpro) enzyme
  • IVM blocks/inhibits human TMPRSS2
  • IVM modulates the NF-kB pathway

Known Mechanism of Action:Brief Explanation:
IVM hinders the binding of the SARS-COV-2 spike protein with the ACE2 receptor on our cellsIvermectin docks with the spike protein & binds to the ACE-2 receptor of our cells, making a barrier that hinders it’s ability to infect a cell.
IVM disrupts the importin (IMP) α/β receptor which is responsible for transmitting viral proteins into the host cell nucleusThese proteins are used by the virus to send messages to our nucleus not to defend itself. Ivermectin disrupts these messages resulting in better cellular defence by our tissues.
IVM disrupts the RdRp enzyme of the virus reducing the virus’s replicationRdRp’s function is to create more Messenger RNA viruses.
IVM disrupts the viral main proteinase – the ‘3-Chymotrypsin Like Protease’ (3CLpro) enzymeWhich controls the activities of the replication process, resulting in the reduction in virus replication.
IVM blocks/inhibits human TMPRSS2Ivermectin was found to strongly and stably bind with TMPRSS2 which indicates that Ivermectin has the potential to disrupt host-virus interaction.
IVM modulates the NF-kB pathwayExerting an Anti-Inflammatory effect.

Ivermectin itself does not attack the SARS-CoV-2 virus. Our body could take care of the virus except that the virus disables the cells defence system. Ivermectin disables the ‘viruses ability’ to take out our defence system (detailed below). If the virus is not suppressing our cells defences, the cell and our neighbouring cells defence system is capable of taking care of the virus. So it works alongside your immune system – removing hinderances in it’s path to allow your immune system to do what it does best.

ACE-2

Ivermectin Docks between the Spike Protein & our cell’s own ACE-2 Receptor

IVM docks between the spike protein and the ACE-2 receptor of our cells, making a barrier that hinders it’s ability to connect to the ACE-2 receptor (making it harder for it to infect that cell). ((Ivermectin Docks to the SARS-CoV-2 Spike Receptor-binding Domain Attached to ACE2)) ((Exploring the binding efficacy of ivermectin against the key proteins of SARS-CoV-2 pathogenesis: an in silico approach)) ((Ivermectin as a potential drug for treatment of COVID-19: an in-sync review with clinical and computational attributes))

How I understand it:

  • SARS-CoV-2 arrives at the cell either by Pinocytosis or Phagocytosis, or by binding with the ACE-2 receptor and fusing with cell membrane.
  • The spike protein (S-protein) has two sub-units, called the S1 and S2.
  • S1 mainly contains the (Receptor Binding Domain = RBD) which is responsible for recognizing the cell surface receptor (our ACE-2 receptor).
  • Ivermectin’s barrier becomes a hinderance for the virus to be able to successfully bind with the ACE-2 receptor and enter the cell.
I modified a screen-capture from YouTube to visualize the ‘concept’, see this image for a closer depiction.
Technical Notes:

IVM hinders the binding of the SARS-COV-2 spike protein with the angiotensin-converting enzyme 2 (ACE2 receptor) on our cells. It docks in the region of leucine 91 of the spike, and histidine 378 of the ACE2 receptor.

The spike (S) protein of SARS-CoV-2, which plays a key role in the receptor recognition and cell membrane fusion process, is composed of two subunits, S1 and S2.

The S1 subunit contains a receptor-binding domain that recognizes and binds to the host receptor angiotensin-converting enzyme 2, while the S2 subunit mediates viral cell membrane fusion by forming a six-helical bundle via the two-heptad repeat domain. ((Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19))

TMPRSS2

IVM Binds with TMPRSS2, inhibiting the entry of the virus into the host cell

IVM blocks/inhibits Transmembrane Protease Serine2 inhibitor (TMPRSS2). ((Exploring the binding efficacy of ivermectin against the key proteins of SARS-CoV-2 pathogenesis: an in silico approach)) ((Molecular Docking Reveals Ivermectin and Remdesivir as Potential Repurposed Drugs Against SARS-CoV-2))

How I understand it:

  • For SARS-CoV-2 to get into our cell, it is first held in place by Heparan Sulfate, then Furin splits the spike to fit to the ACE-2 receptor, then the spike attaches to ACE-2. Once attached, TMPRSS2 cuts a wedge from both the ACE-2 and the Spike, which enables cell entry.
  • TMPRSS2 performs a crucial role in the ACE2-mediated entry in human cells and pathogenesis of SARS-COV-2. TMPRSS2 is a protease.
  • The spike protein (S-protein) has two sub-units, called the S1 and S2.
  • S1 contains a (Receptor Binding Domain = RBD) that locates & binds to our ACE-2 receptor (explained above in the ACE-2 section).
  • S2 contains basic elements needed for the membrane fusion.
  • S2 contains a fusion protein which binds with the cell membrane after priming with TMPRSS2.
  • Ivermectin was found to strongly and stably bind with TMPRSS2 which indicates that Ivermectin has the potential to disrupt host-virus interaction.
  • It was found to be more effective than Remdesivir and lower than HCQ – suggesting the use of either IVM and/or HCQ could be utilized for this function

Technical Notes:

IVM blocks/inhibits human TMPRSS2. (TMPRSS2 performs a crucial role in the ACE2-mediated entry in human cells and pathogenesis of SARS-COV-2).

Ivermectin was found to strongly and stably bind with TMPRSS2 which indicates that Ivermectin has the potential to disrupt host-virus interaction. It was found to be more effective than remdesivir and lower than HCQ – suggesting the use of either IVM and/or HCQ could be utilized for this function).

The viral spike protein binds with the ACE-2 cell surface receptor for entry, while TMPRSS2 triggers its membrane fusion.

The molecular docking of ivermectin with TMPRSS2 suggested an important role of ivermectin in inhibiting the entry of the virus into the host cell, probably by increasing the endosomal pH. Ivermectin efficiently binds to the viral S protein as well as the human cell surface receptors ACE-2 and TMPRSS2; therefore, it might be involved in inhibiting the entry of the virus into the host cell. ((Molecular Docking Reveals Ivermectin and Remdesivir as Potential Repurposed Drugs Against SARS-CoV-2))

TMPRSS2 performs a crucial role in the ACE2-mediated entry in human cells and pathogenesis of SARS-CoV-2.

Therefore, TMPRSS2 could be a therapeutic target and we have studied the interaction between ivermectin and TMPRSS2 protein.

Ivermectin B1a and B1b were found to bind with TMPRSS2.

Binding of ivermectin is majorly orchestrated by the formation of hydrogen bonds and hydrophobic interactions.

Interestingly, the binding of ivermectin to hTMPRSS2 also revealed that ivermectin preferably targets binding zone when S1 protein occupies.

Such a strong interaction indicated toward the potential of ivermectin to disrupt host–virus interaction. Stability of the interaction was verified by molecular dynamic simulation. ((Exploring the binding efficacy of ivermectin against the key proteins of SARS-CoV-2 pathogenesis: an in silico approach))

(IMP) α/β

Ivermectin disrupts the importin (IMP) α/β receptor

IVM disrupts the importin (IMP) α/β receptor which is responsible for transmitting viral proteins into the host cell nucleus. ((An AlphaScreen®-Based Assay for High-Throughput Screening for Specific Inhibitors of Nuclear Import)) ((The importin α/β-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways)) ((Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic)) ((The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro)) ((Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus)) ((An in-silico analysis of ivermectin interaction with potential SARS-CoV-2 targets and host nuclear importin α)) ((Quantitative proteomics reveals a broad‐spectrum antiviral property of ivermectin, benefiting for COVID‐19 treatment)) ((Ivermectin as a Broad-Spectrum Host-Directed Antiviral: The Real Deal?))

How I understand it:

Upon entry to the cell, the virus has the ability to turn off the cell’s defence system.

Normally when a cell is under stress, it produces enzymes to protect itself which also signals the neighbouring cells that it’s under attack which gets them primed and ready to defend themselves. SARS-CoV-2 has the ability to turn that signal off.

When a cell is stressed, it secretes interferon and tumor necrosis factor. These chemical substances helps protect the cell itself, and the neighbouring cells detect this substance, which enables them to get ready.

SARS-CoV-2 blocks our cell from secreting these enzymes by sending a message to the brain of the cell – the nucleus (via our proteins importin (IMP) α/β) telling it not to defend itself (not to make those interferon and tumor necrosis factor).

Ivermectin takes away SARS-CoV-2’s super-power. The reason this virus is so damaging and able to replicate so fast, is because our cells defence system has been shut-down.

Ivermectin disrupts these messages resulting in better cellular defence by our tissues. How does Ivermectin do that?

Ivermectin blocks the binding of the virus message with importin (IMP) α/β) because when Ivermectin is in the cells, it’s already ‘occupying’ those importins.

The result being that the virus can not use importin (IMP) α/β to communicate to the brain of the cell to tell it not send out those enzymes.

Now the nucleus will sense the stress, create the enzymes, warn the neighbouring cells and those enzymes also help protect the cell itself.

This video from Dr Been explains this function – it’s extremely important! Incredible. ((How Ivermectin Helps Against SARS-COV-2? Drbeen Medical Lectures – 26 Nov 2020))

Technical Notes:

Ivermectin acts by inhibiting the host importin alpha/beta-1 nuclear transport proteins, which are part of a key intracellular transport process that viruses hijack to enhance infection by suppressing the host antiviral response.

Human type I interferons (IFNs) are a large subgroup of interferon proteins that help regulate the activity of the immune system.

Interferons bind to interferon receptors. All type I IFNs bind to a specific cell surface receptor complex known as the IFN-? receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chains.

IVERMECTIN prevents viral entry into the nucleus of the cells. The virus attaches on a heterodimer protein Importin α / Importin β-1 which serves as a transport system in order for it to gain entry into the nucleus. Then the virus shuts down the nucleus thereby immune responses against it is practically suppressed.

IVERMECTIN inhibits this heterodimer protein and the virus is prevented from latching onto it and is thus prevented from being transported into the nucleus, thereby disabling the virus from performing this critical function. ((r/IvermectinHowItWorks))

Zoom Screenshot: ‘Ivermectin for COVID-19 Summit’ Illustration of ‘Some’ SARS-CoV-2 virus proteins

We’ve been thinking about the ORF6 protein because in the original SARS virus (SARS-CoV), the ORF6 protein was shown to inhibit IMP α/β by binding and tethering it to the ER (endoplasmic reticulum), so this might be another mechanism by which SARS-CoV-2 is inhibiting (IMP) α/β transport that might be pertinent to Ivermectin’s mechanism of action.

Dr Kylie Wagstaff
Monash Biomedicine Discovery Institute
International Ivermectin for COVID-19 Summit

In Vitro research notes:

Ivermectin binds to Impα (splits the Impα/β1 heterodimer). IVM alters Impα structure – prevents binding to viral proteins or Impβ1. Because of that, Ivermectin has anti-viral activity (in vitro at least) against a range of viruses. ((The 1st International Ivermectin for Covid-19 Summit))

Ivermectin has anti-viral action against the SARS-CoV-2 clinical isolate in vitro, with a single dose able to control viral replication within 24–48 h in our system. We hypothesise that this is likely through inhibiting IMPα/β1-mediatednuclear import of viral protein. ((The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro))

Schematic showing IMPα’s role in nuclear transport of host and viral proteins, and mechanism of inhibition by ivermectin. Jans DA & Wagstaff KM: Cells 2020, 9, 2100 ((Ivermectin as a Broad-Spectrum Host-Directed Antiviral: The Real Deal?))

 RdRp

Ivermectin disrupts the viral RNA dependent RNA Polymerase (RdRP)

IVM disrupts the RdRp enzyme of the virus reducing the virus’s replication (RdRp’s function is to create more Messenger RNA viruses). ((Ivermectin as a promising RNA-dependent RNA polymerase inhibitor and a therapeutic drug against SARS-CoV2: Evidence from in silico studies)) ((The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro)) ((Exploring the binding efficacy of ivermectin against the key proteins of SARS-CoV-2 pathogenesis: an in silico approach)) ((Effective Anti-SARS-CoV-2 RNA Dependent RNA Polymerase Drugs Based on Docking Methods: The Case of Milbemycin, Ivermectin, and Baloxavir Marboxil)) ((Prediction of potential inhibitors for RNA-dependent RNA polymerase of SARS-CoV-2 using comprehensive drug repurposing and molecular docking approach)) ((A Combination of Ivermectin and Doxycycline Possibly Blocks the Viral Entry and Modulate the Innate Immune Response in COVID-19 Patients))

How I understand it:

When the virus binds with ACE-2, it eventually sends the RNA (a strand of instructions) of the virus into our cytoplasm. The viruses RNA is a ‘positive sense RNA’, the ends of which, can directly enter into our Ribosome (our mechanism for building proteins for our own bodies), without needing any manipulation.

Here, I imagine the Viruses RNA to look like a wiggly-worm / ribbon, which acts kind of like the tape of a cassette, and that our Ribosome is the cassette-player that ‘plays’ the tape, and then builds something according to the instructions on the ‘tape’ – but I haven’t seen or heard that analogy used anywhere so I may be way off! This is just how I imagine the concept.

Dr Been ((Updated: Ivermectin Mechanism of Action (MOA) )) explains the Ribosome as if it’s the “Chef”, (and when he said that, I imagined an “Engineer or Builder or Manufacturing Factory”):

Ribosome = a Chef in our cells = that reads the data from the RNA = that uses the recipes to build proteins.

Ribosome is the Engineer/Builder/Factory in our cells. It reads the data from the RNA, that reads the blueprints to builds proteins.

RNA-dependent RNA polymerase”

R (RNA)
d (dependant)
R (RNA)
p (polymerase)

Polymerase means: something that can create Polymers.

RdRp means: something that can “read an RNA strand”.

  • The RNA strand of SARS-CoV-2 instructs our Ribosome to make one large polyprotein, and inside there are many tiny proteins, but these tiny proteins need to be cut out (like out of a jigsaw puzzle). Once the tiny proteins are cut, they become functional.
  • To cut them out of that polyprotein, we need “Proteases”. (Protease = means something that can ‘cut’ a protein). There are proteases both on the outside of the cell and the inside of the cell. There is a protease on the ‘outside’ of the cell which ‘cuts’ the spike protein, and a protease ‘inside’ the cell that ‘cuts’ the tiny proteins out of the polyprotein.
  • The RNA strand of SARS-CoV-2 also instructs our Ribosome to make the RDRP (Once the PolyProteins have been made, and once they have started opening up into smaller enzymes, one of the smaller enzymes created is the RdRp).
  • To make a virus, the virus needs us to create the envelope of the virus, the spike proteins, and also the genome (the genetic structure). The RDRP’s job is to pickup & replicate the genome.
  • This RdRp is the backbone of the viral replication (it essentially creates the “brains” of the newly formed viruses). RDRP’s job = spit out/duplicate/create copies of new RNA strands. It’s function is to make ‘bulk’ ‘messenger RNA’s’ that will go into each new virus as they are assembled. (Every single strand it makes, goes into a newly assembled virus – one strand per new virus).
  • The RDRP enzyme’s function (it’s ‘service’ to the virus) is that it makes the “RNA Copies” (the RNA strands that will replicate throughout the body). The RNA strands are the brains – the “instructions” that go into each newly formed virus which in turn, instructs them to invade more cells and instruct those new cells to create more viruses, and so on.
  • Ivermectin potentially shows that it binds with the RdRp enzyme which will possibly disrupt the virus (by reducing it’s capacity for viral replication). So if we break or disrupt this RDRP enzyme from functioning, the RNA for the newly formed viruses will not be present.
    The Ribosome (our chef/builder/tape player) will still make all the other virus parts, but they will be missing the ‘brain’. Disrupting this function will make the virus useless (although the spike protein can still damage).

Dr. Been has a nice short video that gives a brief explanation of this. ((How Does Ivermectin Work? Mobeen Syed, YouTube -19 Feb 2021))

Technical Notes:

Nice to Know:

  • Ivermectin can disrupt the RDRP.
  • Zinc plus HCQ can also disrupt the RDRP.
    (HCQ can also change the pH of the cell & also disrupts the binding of the virus)
  • Zinc plus Zinc Ionsphore (Quercetin, HCQ, etc.) can also disrupt the RDRP.

Ivermectin can take the place of the Zinc plus HCQ protocol, Ivermectin can also take the place of the expensive drug Remdesivir. Ivermectin plus doxycycline improves pression to more serious illness’s. ((Ivermectin in combination with doxycycline for treating COVID-19 symptoms: a randomized trial))

  • RdRp is an essential enzyme involved in the replication of RNA viruses including SARS-CoV-2. Several anti-viral drugs have been developed targeting this enzyme for treating infections like Hepatitis C, Zika and other coronaviruses.
  • Significant binding of Ivermectin with RdRp indicate its role in the inhibition of the viral replication and ultimately impeding the multiplication of the virus.
  • IVM disrupts the RdRp enzyme of the virus reducing the virus’s replication. (RdRp’s function is to create more Messenger RNA viruses)
  • Zinc disrupts the RDRP enzyme (but it needs a Zinc iophore like HCQ or Quercetin to bring more zinc into the cell, else not enough zinc enters the cell to be able to disrupt this enzyme)

3CLpro

Ivermectin blocks more than 85% of 3CLpro activity of SARS-CoV-2

IVM disrupts the viral main proteinase – the ‘3-Chymotrypsin Like Protease’ (3CLpro) enzyme. (which controls the activities of the replication process) resulting in the reduction in virus replication. ((Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents)) ((Drug repurposing studies targeting SARS-CoV-2: an ensemble docking approach on drug target 3C-like protease (3CLpro) ))

How I understand it:

  • The 3CLpro enzyme, also called Main protease (Mpro), is indispensable to the viral replication and infection process
  • When the virus is in the cytoplasm, it releases its messenger RNA, which is picked-up by the Ribosome. Ribosome translates that into a large protein called Polyprotein. (All the enzymes of the virus are created in one large precursor “polyprotein”, which is subsequently cleaved by viral protease to form functionally viral components).
  • Some enzymes break off of this polyprotein by themselves (auto-proteolysis), then they further help break-down the main PolyProtein into individual enzymes.
  • One of the proteins that breaks off by itself, is called Mpro or 3CLpro. This protein is a Protease, which then works on the main PolyProtein to liberate the remaining enzymes for the virus, which will then start replicating.
  • Ivermectin “Binds” to the 3CLpro enzyme, thereby suppressing the 3CLpro enzyme, resulting in the remaining virus production becoming stalled.

NF-kB

Ivermectin may inhibit LPS-induced production of inflammatory cytokines by blocking NF-kB pathway

IVM modulates the NF-κB pathway. (exerting an Anti-Inflammatory effect). ((Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase activation pathway)) ((Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice))

How I understand it:

  • NF-κB is found in almost all cell types and is involved in cellular responses to stimuli such as stress, cytokines (Cytokines cause Inflammation), free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens.
  • NF-κB is a protein complex that controls transcription of DNA, cytokine production and cell survival.
  • NF-κB consist of 2 proteins present on the cell, which are kept inactivated by iKBa.
  • When a signal arrives from the cell or some stress occurs or some reactive oxygen species are produced or the cell is under attack by a virus, the NF-kB protein complex is activated. (When an immune cell finds a virus or a bacteria, there is production of NF-kB and Cytokines are produced).
  • The activation causes both the IK Beta and the NF-kB to be separated.
  • NF-kB then goes into the nucleus, and from there, various gene expressions occur and various cell responses occur.
  • Ivermectin can actually dock with the NF-kB and disrupt its function. In the presence of Ivermectin, the inflammatory system is modulated; (thereby reducing the inflammation response).

Technical Notes:

What is the NF-κB pathway? NF-κB (nuclear factor kappa light chain enhancer of activated B cells) is a family of highly conserved transcription factors that regulate many important cellular behaviours, in particular, inflammatory responses, cellular growth and apoptosis. NF-κB is also involved in diseases such as cancer, arthritis and asthma. ((What is the NF-κB pathway?))

Ivermectin

The growing list of studies demonstrating the anti-inflammatory properties of ivermectin include its ability to inhibit cytokine production after lipopolysaccharide exposure, downregulate transcription of NF-kB, and limit the production of both nitric oxide and prostaglandin E2. ((Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19))

Avermectin

Avermectin significantly inhibits NF-kappaB p65 translocation into the nucleus and inhibits JNK and p38 phosphorylation protein expression.

Therefore, avermectin may inhibit LPS-induced production of inflammatory cytokines by blocking NF-kappaB and MAP-kinase in RAW 264.7 cells.((Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase activation pathway))

Other points that I still don’t understand

Ivermectin also possess significant binding affinity with NSP3, NSP10, NSP15 and NSP16 which helps virus in escaping from host immune system. ((A Combination of Ivermectin and Doxycycline Possibly Blocks the Viral Entry and Modulate the Innate Immune Response in COVID-19 Patients))

Ivermectin significantly inhibited ADP Ribose Phosphatase (NSP3), Endoribonuclease (NSP15) and methyltransferase (NSP10-NSP16 complex) of SARS-CoV-2 which were involved in the virus escape from the host innate immune system. ((A Combination of Ivermectin and Doxycycline Possibly Blocks the Viral Entry and Modulate the Innate Immune Response in COVID-19 Patients))

Another mechanism of action by which ivermectin is believed to act involves transmembrane receptor CD147. CD147 along with ACE-2 has been recognized as a key binding site for SARS-CoV-2 spike protein. The potential for major dose–response gains is assessed on the basis of studies that indicate that ivermectin shields SARS-CoV-2 spike protein which binds to CD147 and ACE-2. ((Ivermectin as a potential drug for treatment of COVID‑19: an in‑sync review with clinical and computational attributes)) ((Ivermectin for COVID-19 Treatment: Clinical Response at Quasi-Threshold Doses Via Hypothesized Alleviation of CD147-Mediated Vascular Occlusion))

7 Leaders & 18 other Warriors
(Collection of Ivermectin Literature Translated from Hungarian)

The following was posted today (July 23 2021) by Attila Merényi : founder of the Ivermectin MD Team Facebook group – which started as a group of medical health professionals who are using Ivermectin to treat COVID-19 (but now they allow the general public to join). I usually like to double-check every claim made – generally not trusting anyone else’s research until I fully understand it by cross-referencing, but in this case, these guys know a lot more about Ivermectin than I do, and I don’t have time right now to go through it as my focus is elsewhere, but I will go through the additional references and see if it corresponds with anything I might of missed above and update when I have more time.

Note: English is not his first language, and the post was written in Hungarian but we requested an English version and he translated it for us.

I’m going to make the assumption that the “Hungariver warrior (and corresponding titles he chose for each point)’ is more relevant as context in his country of Hungary.

Here is his post & list of references:

Click to Expand


The 7 LEADERS and 18 other WARRIORS ((TWENTY-FIVE HUNGARIVER WARRIOR https://www.facebook.com/groups/3595465843801899/posts/4873635129318291/))

(literature collected for my medical colleagues)

  1. ÁLMOS
    The direct action of Ivermectin against SARS-CoV-2 is to prevent entry into the cell. It is able to bind to the S protein of the virus via the leucine at position 91 of the protein on the one hand in the extracellular phase, – the highest binding affinity for the predicted active site of the S-glycoprotein (Mol Dock score ?140,584) and protein-ligand interactions ). From the target cell side, it binds to the ACE2 molecule, which serves as the receptor for the virus, through Histidine at position 378. This mechanism inhibits the binding of the virus to the cells of the attacked organism, thus slowing down the spread of the virus within the organism.
  2. OND
    It is a direct action against the virus, but it can also directly inhibit the function of the virus’s RNA-dependent RNA polymerase (RdRP): both the binding of the enzyme to the template RNA and the elongation of the initiated RNA chains. The second of these 5 docking properties is the significant binding affinity for the predicted active site of the viral RdRp protein (MolDock score ?149.9900) and protein-ligand interactions (MolDock score ?147.608). It formed H-bonds with only two amino acids: Cys622 and Asp760.
  3. BULCSÚ
    Direct action against the virus, third docking property, highest binding affinity (MolDock score ?212.265) for the predicted active site of nsp14.
  4. KOPPÁNY
    Direct action against the virus, fourth docking property, highest binding affinity for the active site of TMPRSS2 protein (MolDock score ?174,971) and protein-ligand interactions (MolDock score ?180,548). In addition, it formed five H-bonds with amino acid residues Cys297, Glu299, Gln438, Gly462, and Gly464 present at the predicted active site of the TMPRSS protein.
  5. VAZUL
    Direct action against the virus, fifth docking property, the free binding energy of the spike protein (open) was higher in Ivermectin (?398,536 kJ / mol) than in remdesivir (?232,973 kJ / mol).
    Note1: Ivermectin effectively uses viral spike protein, major protease, replicase, and human TMPRSS2 receptors as the most expedient targets to achieve antiviral efficacy by disrupting binding. Because Ivermectin exploits both viral and human protein targets, this may be behind the excellent in vitro efficacy against SARS-CoV-2.
    Note 2: The development of virus vaccines is focused on spike protein biology (virus targeted) and recently documented “vaccine escape strains” are of concern. In such a situation, the Ivermectin is a target for both the virus and the host and may therefore act as a potential therapy against these new strains, which may “avoid” the immunity provided by the vaccine.
  6. EL?D
    Direct action against the virus binds intracellularly to an importin ? / ?1 transport protein complex, which is required for viral replication. This complex delivers viral proteins to the nucleus that are required for the synthesis of viral RNA and for blocking the interferon-mediated immune response at the cellular level. The broad-spectrum antiviral effect of Ivermectin is based on this mechanism.
    Inside the cell, the nuclear transport of proteins into and out of the nucleus depends on the signal and is mediated by the Importin (IMP) superfamily of proteins that exist in ? and ? forms. It exists as an IMP? / ?1 heterodimer, with an “IBB” (IMP ?-binding) site above IMP ?, which binds to IMP ?1 in “load recognition” of IMP?. The SARS-CoV-2 virus tends to “load” its proteins into the host protein IMP ? / ?1 heterodimer (importin) upon entry into the host cell to enter the nucleus through the nuclear pore complex. Upon entry, the importin molecule is detached, while the viral viral protein diverts the host cell machinery and inhibits the release of interferon (an antiviral substance released by an infected cell). to warn surrounding cells of an ongoing virus attack). As a result, the surrounding cells become “unsuspecting victims” of the virus, and the infection continues while the virus avoids recognizing immune cells. In the presence of viral infection, Ivermectin targets and binds to the IMP? component of the ? / ?1 heterodimer of IMP, preventing interaction with IMP ?1 and then blocking nuclear transport of viral proteins. This allows the cell to perform a normal antiviral response. In such a case, it should be noted that Ivermectin activity here is virostatic, i.e., it neutralizes the virus by competing for the same receptor.
  7. TAS
    Direct action against the virus as an ionophore. Ionophores are molecules that typically have a hydrophilic pocket that forms a specific binding site for one or more ions (usually cations) while its outer surface is hydrophobic, so that the complex thus formed can cross cell membranes, affecting hydroelectrolyte balance. It is hypothesized that two Ivermectin molecules may react with each other in a head-to-tail mode to form a complex that may be considered suitable. These ionophores allow the virus to be neutralized in the early stages of infection before it adheres to host cells and enters so that their biochemical machines can be used to produce other virus particles. Thus, the Ivermectin dimeric form creates an apolar structure with a polar pocket inside, thus acting as an ionophore, it can introduce antiviral zinc ions into the cytoplasm alone, either from the intercellular space or from the zinc stores of the endoplasmic reticulum.
  8. LEHEL
    Action against viral replication in the host cell, a general antiviral effect that deserves a special fighter, i.e., a general antiviral effect, including RNA viruses such as Zika virus (ZKV), Dengue virus, yellow fever virus (YFV), and Western blight. Nile virus (WNV), Hendra virus (HEV), Newcastle virus, Venezuelan equine encephalitis virus (VEEV), Chikungunya virus (CHIKV), Semliki Forest virus (SFV) and Sindbis virus (SINV), avian influenza A virus, swine reproductive and respiratory syndrome virus (PRRSV), human immunodeficiency virus type 1, and DNA viruses such as equine herpesvirus type 1 (EHV-1) and pseudorabies virus (PRV).
  9. BUDA
    Action against viral replication in the host cell, inhibition of virus replication and assembly. Virus-infected Vero / hSLAM cells “in contact” with a 5 ?M diver showed a 5,000-fold decrease in viral RNA within 48 hours compared to the control group. This study provided debile opinions on whether Ivermectin cannot achieve the therapeutic effect of COVID-19 with routine dosing. In contrast, using the modeling approach, Arshad and colleagues predicted lung accumulation in the Ivermectin at well ten-fold than the EC50. This likelihood leaves further research open before reaching higher lung tissue concentrations in the iver, especially for respiratory infections. Another study showed the best binding interaction between Ivermectin and RdRp of -9.7 kcal / mol, suggesting inhibition of viral replication. RdRP in nsp12 is the center of the coronavirus replication and transcriptional complex and has been proposed as a promising drug target because it is a key enzyme in the viral life cycle for both viral genome replication and subgenomic mRNA transcription (sgRNAs). The Ivermectin binds to the viral rdrp and interferes with it. The highly efficient binding of Ivermectin to nsp14 reinforces its role in inhibiting viral replication and assembly. It is well known that nsp14 is essential for transcription and replication. It acts as a corrective exoribonuclease and plays a role in limiting viral RNA through methyltransferase activity [35]. In addition, the highly efficient binding of Ivermectin to viral N-phosphoprotein and M-protein suggests that it plays a role in inhibiting viral replication and assembly.
  10. ÁRPÁD
    Action against viral replication in the host cell by interfering with the post-translational process of viral polyproteins. Once it enters the host cell, the viral RNA is translated by the host ribosome into a large “polyprotein”. Some enzymes are cleaved by autoproteolysis of the polyprotein and further assist other proteins in their cleavage and replication function. One such enzyme, 3 chymotrypsin-like proteases (3’cl pro / Mpro), is responsible for working with this polyprotein and for other proteins to “library” and replicate the virus. The Ivermectin binds to and breaks down this enzyme. In addition, it binds efficiently to both proteins, Mpro and, to a lesser extent, viral PLpro; therefore, it plays a role in preventing post-translational processing of viral polyproteins.
  11. CSANÁD
    Action against viral replication in the host cell, effect on caryopherin (KPNA / KPNB) receptors. Caryopherin-?1 (KPNA1) is essential for the nuclear transport of transcriptional signal transducers and activators (STAT1) 1, and the interaction between STAT1 and KPNA1 (STAT1 / KPNA1) contains a non-classical nuclear localization signal (NLS). Ivermectin inhibits KPNA / KPNB1-mediated nuclear import of viral proteins, allowing the cell to perform a normal antiviral response.
  12. ETE
    Action against host targets important for inflammation, action at the level of interferon (INF). These virus-infected cells release interferons that bind to IFN receptors in neighboring cells and alert them to viral attack. IFN-I and IFN-III receptors then further activate members of the JAK-STAT family. Once introduced into the host cell, the virus diverts the host cell machinery and works to antagonize the normal interferon-mediated host cell antiviral response. SARS-CoV-2 proteins such as ORF3a, NSP1, and ORF6 inhibit IFN-I signaling. As a result, cells surrounding cells infected with the virus are “unable” to receive “critical and protective IFN signals,” allowing the virus to multiply and spread unhindered. This is one of the main reasons why COVID-19 infection is clinically “difficult to detect” at this stage. Ivermectin has been shown to promote the expression of several IFN-associated genes, such as IFIT1, IFIT2, IF144, ISG20, IRF9 and OASL.
  13. HETÉNY
    Action against host targets important for inflammation, action on Toll-like receptors. Upon entry of the virus, intracellular pattern recognition receptors (PRRs) on host cells are responsible for detecting viral attack. The virus activates one such PRR, Toll-like receptors (TLRs). These receptors are on a variety of immune cells that help find and bind to the pathogen. Activation of TLRs causes oligomerization, further activating downstream interferon regulatory factors (IRFs) and INF factor-inducing nuclear factor-kappa B (NF-kB) transcription factors. Ivermectin plays a role in blocking the activation of the NF-?B pathway and inhibiting TLR4 signaling.
  14. KEVE
    Action against host targets important for inflammation, action on the nuclear factor-?B (NF-?B) pathway. Activation of the kappa light chain enhancer of activated factor B cells (NF-?B) induces the expression of various anti-inflammatory genes, including genes encoding cytokines and chemokines. At very low doses of iver, which did not induce cytotoxicity, it drastically reversed the resistance of tumor cells to chemotherapeutic drugs in vitro and in vivo by inhibiting the transcription factor NF-?B. It was also allegedly inspired by Sarkadi’s counter-article because this effect harms his business interests. I’m not saying, I just heard. ? Ivermectin also inhibits the production of lipopolysaccharide (LPS) -induced inflammatory cytokines by blocking the NF-?B pathway. Therefore, the use of Ivermectin may be useful in the intensive care unit, where there is a higher chance of bacterial infections.
  15. HUBA
    In addition to the direct antiviral effect, Ivermectin is also able to inhibit virus-induced pathophysiological processes in the late phase of Covid-19. SARS-CoV-2 potentiates the STAT3-mediated inflammatory cascade response, triggering cytokine storm formation. The Ivermectin is able to block the STAT3 cascade, thus inhibiting the abnormal immune response.
    So this is also an action against host targets important for inflammation, action on the JAK-STAT route. There is a strong association between viral load, disease severity, and progression. COVID-19 not only causes flu-like symptoms such as fever, dry cough, but can also lead to widespread pulmonary thrombosis with microangiopathy, increase D-dimer levels, cause lymphopenia, and significantly increase inflammatory prochinytins and chemokine production. SARS-CoV-2 shows structural similarity to SARS-CoV-1. Several SARS-CoV-1 proteins antagonize the antiviral activity of IFNs and the downstream JAK (Janus kinase) -STAT signaling pathways they activate. JAK family kinases have a variety of functions in the areas of ontogenicity, immunity, chronic inflammation, fibrosis, and cancer.
    Host proteins such as signal transducers and transcriptional activators (STAT) and NF-?B enter the nucleus through nuclei embedded in the IMP? / ?1 heterodimer-mediated nucleus and play a role in the pathogenesis of COVID-19. The SARS ORF6 supplement antagonizes STAT1 function by sequencing nuclear import factors on the coarse endoplasmic reticulum / Golgi membrane. Another article refers to SARS-CoV-2-mediated inhibition of IFN and STAT 1 by switching to the later STAT 3 dominant signaling network, which may result in almost all clinical features of COVID-19.
    It is important to understand the relationship between STAT-3 upregulation and the consequences of COVID-19 and the role of Ivermectin in STAT-3 inhibition. STAT-3 acts as a “central node” that mediates the harmful COVID-19 cascade. In the lung, STAT-3 activates Hyaluronan synthase-2, leading to the deposition of hyaluronan, causing diffuse alveolar damage. Damaged alveolar type 2 cells express PAI-1 (plasminogen activator inhibitor-1). In addition, hypoxia due to diffuse alveolar damage causes regulation of PAI-1 through HIF-1a. STAT-3 also directly activates PAI-1. Simultaneous activation of PAI-1 and STAT-3 inhibits t-PA and urokinase-type plasminogen activator, leading to thrombin formation in capillaries. PAI-1 also binds to TLR-4 receptors on macrophages, further activating the NF-?B pathway.
    The “cytokine storm” characteristic of severe COVID-19 involves STAT-3-mediated upregulation of proinflammatory cytokines, TNF? and IL-6, in macrophages. In addition, STAT-3 induces a C-reactive protein that regulates PAI-1 levels. STAT-3 is directly responsible for activating IL-6 gene transcription, which further increases the growth of TGF-?, which causes pulmonary fibrosis. PD-L1 receptors present in endothelial cells are activated by STAT-3, which causes T-cell lymphopenia. Ivermectin inhibits STAT-3 through direct inhibition, preventing the consequences of COVID-19.
  16. CSABA
    Action against host targets important for inflammation, action on P21 activated Kinase 1 (PAK-1). P21 activated kinase1 (PAK1) physically binds to JAK1 and STAT3, and the resulting PAK1 / STAT3 complex activates cytokine storm-mediated IL-6 gene transcription in COVID-19. Ivermectin suppresses Akt / mTOR signaling and promotes ubiquitin-mediated degradation of PAK-1, thereby impairing STAT-3 activity and reducing IL-6 production.
  17. TAKSONY
    Action against host targets important for inflammation at interleukin-6 (IL-6) levels. Ivermectin suppresses IL-6 and TNF? production, the two main components of the harmful cytokine storm induced by SARS-CoV-2, and “dramatically reduces” the IL-6 / IL-10 ratio that modulates the outcome of infection.
  18. ZSOLT
    Action against host targets important for inflammation, effect on allosteric modulation of the P2X4 receptor. P2X receptors are cation-selective channels, gate extracellular ATP, and mediate a number of functions in health and disease. Of the seven subunits of P2X receptors, P2X4 is the most sensitive to the iver. Positive allosteric modulation of P2X4 inversely enhances ATP-mediated secretion of CXCL5 (an anti-inflammatory chemokine). CXCL5 is a chemoattractant molecule that is expressed in inflammatory cells of various tissues and modulates neutrophil chemotaxis and chemokine removal.
  19. VAJK
    Action against host targets important for inflammation, action against the high mobility group, HMGB1. It is released by damaged cells that act as agonists of the TLR4 receptor, thereby mediating COVID-19-associated pneumonia. Ivermectin inhibits HMGB1.
  20. ÖRS
    It is an action against host targets important for inflammation and acts as an immunomodulator in lung tissue and olfactory tissue. Ivermectin dramatically reduced the IL-6 / IL-10 ratio in lung tissue, likely to result in a more favorable clinical appearance. Odor loss has been reported as a common symptom of COVID-19. Interestingly, the majority of Indian patients regained their sense of smell after a short period of anosmosis during their clinical course. Ivert is used in India as one of the first line drugs for COVID-19 treatment. It is hypothesized that Ivermectin may play a role in reducing SARS-CoV-2-induced olfactory deficiency.
  21. LEVENTE
    Action against host targets important for inflammation as an anti-inflammatory. The mechanism of the anti-inflammatory effect of Ivermectin has been explained by inhibition of cytokine production by lipopolysaccharide-provoked macrophages, blockade of NF-?B activation, and inhibition of stress-activated JNK and p38 MAP kinases, and TLR4 signaling. In addition, iv significantly reduced immune cell uptake, cytokine production in bronchoalveolar lavage fluid, IgE and IgG1 secretion, and goblet cell hypersecretion.
  22. BERÉNY
    Action on other host targets with plasmin and Annexin A2. Annexin A2 can be linked to the pathophysiology of COVID-19. Annexin A2 acts as a co-receptor for the conversion of plasminogen to plasmin in the presence of t-PA. Elevated plasmin levels are found in comorbid conditions and are also responsible for the early stages of viral infection. Plasmin leads to direct activation of STAT-3, which causes detrimental COVID-19 consequences. Ivermectin directly inhibits STAT-3 and may play a role in inhibiting COVID-19 complications.
  23. TÖHÖTÖM
    Action on other host targets, CD147 on RBC. By binding to endothelium in the blood vessels, CD147 on the surface of platelets and red blood cells in the bloodstream, Ivermectin prevents the virus from attaching to these receptors, thus preventing the formation of virus-mediated micro- and macrothrombi. Thus, the transmembrane receptor CD147 and ACE-2 present on red blood cells (RBCs) are a jointly recognized fact that the virus is a key binding site for spike protein. The virus is not internalized into the RBC, but such binding can lead to clumping. The Ivermectin binds to the viral S protein, so binding to CD147 is not achieved. This effect may be useful in advanced stages of COVID-19 associated with coagulation / thrombotic events.
  24. SZABOLCS
    Action at other host targets, i.e., mitochondrial ATP in the heart under hypoxia. SARS-CoV-2 is a well-known cause of acute myocardial damage and chronic damage to the cardiovascular system in active infection as well as in long covids. Ivermectin enhances mitochondrial ATP production by inducing Cox6a2 expression and maintains mitochondrial ATP under hypoxic conditions, preventing pathological hypertrophy and improving cardiac function.
  25. KOND
    Ivermectin also inhibits the activity of the virus-specific RNA helicase enzyme, thus preventing the formation of the biologically active configuration of the viral RNA, ie the formation of non-infectious virions.

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Penny... on Health
Penny... on Health

DISCLAIMER: The information on this website is not medical science or medical advice. I do not have any medical training aside from my own research and interest in this area. The information I publish is not intended to diagnose, treat, cure or prevent any disease, disorder, pain, injury, deformity, or physical or mental condition. I just report my own results, understanding & research.