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: Jun 16, 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 (01) (02) (03)
  2. a treatment (04) (05) (06) (07) (08)
  3. on long-covid (depending on what caused the long-covid) (09) (10)
  4. and continues to work as a preventative/treatment on the new Variants (11) (12) (13) (14)

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” (15) 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. (16) (17)

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). (18) (19) (20)

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-domains, 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. (21)

Screenshot from Prof. Morimasa Yagisawa’s presentation during a virtual interview on May 6, 2021. (22) (23)

TMPRSS2

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

IVM blocks/inhibits Transmembrane Protease Serine2 inhibitor (TMPRSS2). (24) (25)

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. (26)

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. (27)

(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. (28) (29) (30) (31) (32) (33) (34) (35)

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. (36)

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. (37)

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. (38)

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. (39)

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 (40)

 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). (41) (42) (43) (44) (45) (46)

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 (47) 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. (48)

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. (49)

  • 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. (50) (51)

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). (52) (53)

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. (54)

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. (55)

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.(56)

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. (57)

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. (58)

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. (59) (60)

References[+]

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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.