Table 1.
A list of studies demonstrating the probable mechanisms of ivermectin (IVM) against SARS-CoV-2
| Main role of ivermectin against SARS-CoV-2 | Study authors | Study year | References |
|---|---|---|---|
| A. Direct action on SARS-CoV-2 | |||
| Level 1: Action on SARS-CoV-2 cell entry | |||
| IVM docks in the region of leucine 91 of the spike protein and histidine 378 of the ACE-2 receptor | Leher et al. | 2020 | [21] |
| IVM has the highest binding affinity to the predicted active site of the S glycoprotein; Considerable binding affinity to the predicted active site of the SARS-CoV-2 RdRp protein; Highest binding affinity to the predicted active site of nsp14; highest binding affinity to the active site of the TMPRSS2 protein | Eweas et al. | 2021 | [22] |
| IVM utilizes viral spike protein, main protease, replicase, and human TMPRSS2 receptors as the most possible targets for executing its antiviral efficiency by disrupting binding | Choudhury et al. | 2021 | [23] |
| Level 2: Action on importin (IMP) superfamily | |||
| in presence of a viral infection, IVM targets the IMPα component of the IMP α/β1 heterodimer and binds to it, preventing interaction with IMP β1, subsequently blocking the nuclear transport of viral proteins | Yang et al. | 2020 | [25] |
| Level 3: Action as an ionophore | |||
| Two ivermectin molecules, reacting with each other in a “head-tail” mode, can create a complex suitable to be considered as an ionophore. These allow neutralizing the virus at an early stage of the infection before it adheres to the host cells and enters it | Rizzo | 2020 | [27] |
| Ivermectin acts as an ionophore by chloride channel upregulation to generate apoptosis and osmotic cell death |
Dueñas-González et al., Dominguez-Gomez et al. |
2021, 2018 |
[28], [29] |
| B. Action on host targets for viral replication | |||
| Level 4: Action as an antiviral | |||
| IVM has antiviral properties against other viruses including the RNA viruses such as Zika virus (ZKV), dengue virus, yellow fever virus (YFV), and West 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, porcine reproductive and respiratory syndrome virus (PRRSV), human immunodeficiency virus type 1 as well as DNA viruses such as equine herpesvirus type 1 (EHV-1) and pseudorabies virus (PRV) | Heidary et al. | 2020 | [30] |
| IVM acts as an inhibitor of HIV-1 nuclear protein transfer | Wagstaff et al. | 2011 | [31] |
| IVM causes a decrease in viral gene expression in BKPyV due to inhibition of nucleus entry | Bennett et al. | 2015 | [32] |
| IVM demonstrated IMP α/β-dependent nuclear transfer inhibition and reduced virus replication in a dose-dependent manner for BoHV-1 | Raza et al. | 2020 | [33] |
| Level 5: Action on viral replication and assembly | |||
| In Vero/hSLAM cells infected with the SARS-CoV-2 virus when “exposed” to 5 µM IVM showed a 5000-fold reduction in viral RNA at 48 h when compared to the control group | Caly et al. | 2020 | [34] |
| Utilizing modeling approach, predicted lung accumulation of ivermectin over ten times higher than EC 50 | Arshad et al. | 2020 | [35] |
| Best binding interaction between IVM and RNA-dependent RNA polymerase (RdRp) | Swargiary et al.a | 2020 | [37] |
| Highly efficient binding of IVM to nsp14 | Ma et al. | 2015 | [39] |
| Highly efficient binding of IVM to the viral N phosphoprotein and M protein | Eweas et al. | 2021 | [22] |
| Level 6: Action on posttranslational processing of viral polyproteins | |||
| IVM binds to both proteins, Mpro, and to a lesser extent to PLpro of SARS-CoV-2 | Eweas et al. | 2021 | [22] |
| IVM inhibits 3 chymotrypsin-like proteases | Mody et al. | 2021 | [40] |
| Level 7: Action on karyopherin (KPNA/KPNB) receptors | |||
| IVM inhibits the KPNA/KPNB1- mediated nuclear import of viral proteins | Caly et al. | 2020 | [34] |
| C. Action on host targets for inflammation | |||
| Level 8: Action on interferon (INF) levels | |||
| IVM promotes the expression of several IFN-related genes, such as IFIT1, IFIT2, IF144, ISG20, IRF9, and OASL | Seth et al. | 2016 | [45] |
| Level 9: Action on Toll- like receptors (TLRs) | |||
| IVM blocks activation of NF-kappa B pathway and inhibition of toll-like receptor 4 (TLR4) signaling | Zhang et al. | 2008 | [47] |
| Level 10: Action on nuclear factor-κB (NF-κB) pathway | |||
| IVM at its very low dose, which did not induce cytotoxicity, drastically reversed the resistance of tumor cells to the chemotherapeutic drugs both in vitro and in vivo by inhibition of the transcriptional factor NF-κB. | Jiang et al. | 2019 | [49] |
| IVM inhibits lipopolysaccharide (LPS)-induced production of inflammatory cytokines by blocking the NF-κB pathway and improving LPS-induced survival in mice | Zhang et al. | 2008 | [47] |
| Level 11: Action on the JAK-STAT pathway, PAI-1 and COVID-19 sequalae | |||
| IVM inhibits STAT-3, SARS-CoV-2-mediated inhibition of IFN and STAT 1, with the subsequent shift to a STAT-3- dominant signaling network that could result in almost all of the clinical features of COVID-19; STAT-3 acts as a “central hub” that mediates the detrimental COVID-19 cascade | Matsuyama et al. | 2020 | [44] |
| STAT-3 induces a C-reactive protein that upregulates PAI-1 levels. Ivermectin inhibits STAT-3 | Matsuyama et al. | 2020 | [44] |
| The PD-L1 receptors present on the endothelial cells are activated by STAT-3 causing T cell lymphopenia. IVM inhibits STAT-3 through direct inhibition | Matsuyama et al. | 2020 | [44] |
| Level 12: Action on P21 activated kinase 1 (PAK1) | |||
| IVM suppresses the Akt/mTOR signaling and promotes ubiquitin-mediated degradation of PAK1 hence compromising STAT-3 activity and decreasing IL-6 production | Dou et al. | 2016 | [59] |
| Level 13: Action on Interleukin-6 (IL-6) levels | |||
| IVM suppressed IL-6 and TNFα production | Zhang et al. | 2008 | [47] |
| IVM “dramatically reduced” IL-6/IL-10 ratio modulating infection outcomes | De Melo et al. | 2020 | [60] |
| Level 14: Action on allosteric modulation of P2X4 receptor | |||
| Positive allosteric modulation of P2X4 by IVM enhances ATP-mediated secretion of CXCL5 | Layhadi et al. | 2018 | [63] |
| Level 15: Action on high mobility group box 1 (HMGB1) | |||
| Ivermectin inhibits HMGB1 | Juarez et al. | 2018 | [65] |
| Level 16: Action as an immunomodulator on lung tissue and olfaction | |||
| No olfactory deficit was observed in IVM-treated females; IVM dramatically reduced the IL-6/IL-10 ratio in lung | De Melo et al. | 2020 | [60] |
| Level 17: Action as an anti-inflammatory | |||
| Anti-inflammatory action of IVM was explained as inhibition of cytokine production by lipopolysaccharide challenged macrophages, blockade of activation of NF-kB, and the stress-activated MAP kinases JNK and p38, and inhibition of TLR4 signaling | Zhang et al. | 2008 | [47] |
| Ci et al. | 2009 | [67] | |
| Yan et al. | 2011 | [68] | |
| Immune cell recruitment, cytokine production in bronchoalveolar lavage fluid, IgE, and IgG1 secretion in serum as well as hyper-secretion of mucus by goblet cells was reduced significantly by IVM | Yan et al. | 2011 | [68] |
| D. Action on other host targets | |||
| Level 18: Action on plasmin and annexin A2 | |||
| Annexin acts as a coreceptor for the conversion of plasminogen to plasmin in the presence of t-PA. increased levels of plasmin leads to direct activation of STAT-3 | Zaidi et al. | 2020 | [69] |
| IVM directly inhibits STAT-3 and could play a role in the inhibition of COVID-19 complications | Matsuyama et al. | 2020 | [44] |
| Level 19: Action on CD147 on the RBC | |||
|
The SARS-CoV-2 does not internalize into the red blood cells but such attachments can lead to clumping. IVM binds to the S protein of the SARS-CoV-2 virus making it unavailable to bind with CD147 |
Scheim et al. | 2020 | [70] |
| Level 20: Action on mitochondrial ATP under hypoxia on cardiac function | |||
| IVM increased mitochondrial ATP production by inducing Cox6a2 expression and maintains mitochondrial ATP under hypoxic conditions. This prevents pathological hypertrophy and improves cardiac function | Nagai et al. | 2017 | [72] |
aAvailable as preprint