A new paper explains The mechanisms of action of Ivermectin against SARS-CoV-2: An evidence-based clinical review article June 2021The Journal of Antibiotics by Asiya Zaidi and Puya Dehgani Mobaraki H/T Jo Nova. Beware the Big Pharma has already got the article retracted elsewhere, so this link may not last long. Excerpt in italics with my bolds.
Considering the urgency of the ongoing COVID-19 pandemic, detection of various new mutant strains and future potential re-emergence of novel coronaviruses, repurposing of approved drugs such as Ivermectin could be worthy of attention. This evidence-based review article aims to discuss the mechanism of action of ivermectin against SARS-CoV-2 and summarizing the available literature over the years. A schematic of the key cellular and biomolecular interactions between Ivermectin, hostcell, and SARS-CoV-2 in COVID-19 pathogenesis and prevention of complications have been proposed.
Summary (from Jo Nova)
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 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.
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 is a multipronged anti-inflammatory
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.
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”.
Fig. 1 A schematic of the key cellular and biomolecular interactions between Ivermectin, host cell, and SARS-CoV-2 in COVID19 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 tPA. 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 SARSCoV-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.
ACE-2 angiotensin-converting-enzyme 2,
TLR Toll-like receptor,
t-PA tissue-like plasminogen activator,
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
The role of Ivermectin against the SARS-CoV-2 virus
The targets of activity of Ivermectin can be divided into the following four groups.
The direct “antiviral targets” may be useful in the early stages while the anti-inflammatory targets might be addressed in the later stages of the disease.
A. Direct action on SARS-CoV-2
Level 1: Action on SARS-CoV-2 cell entry
Level 2: Action on Importin (IMP) superfamily
Level 3: Action as an Ionophore
B. Action on host targets important for viral replication
Level 4: Action as an antiviral
Level 5: Action on viral replication and assembly
Level 6: Action on post-translational processing of viral polyproteins
Level 7: Action on Karyopherin (KPNA/KPNB) receptors
C. Action on host targets important for inflammation
Level 8: Action on Interferon (INF) levels
Level 9: Action on Toll- like-Receptors (TLRs)
Level 10: Action on Nuclear Factor-κB (NF-κB) pathway
Level 11: Action on the JAK-STAT pathway, PAI-1 and COVID-19 sequalae
Level 12: Action on P21 activated Kinase 1 (PAK-1)
Level 13: Action on Interleukin-6 (IL-6) levels
Level 14: Action on allosteric modulation of P2X4 receptor
Level 15: Action on high mobility group box 1 (HMGB1),
Level 16: Action as an immunomodulator on Lung tissue and olfaction
Level 17: Action as an anti-inflammatory
D. Action on other host targets
Level 18: Action on Plasmin and Annexin A2
Level 19: Action on CD147 on the RBC
Level 20: Action on mitochondrial ATP under hypoxia on cardiac function