Table 2 A list of studies demonstrating the role of Ivermectin (IVM) on SARS-CoV-2

From: The mechanisms of action of Ivermectin against SARS-CoV-2: An evidence-based clinical review article

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 ACE2 receptor Leher et al. 2020 [22]
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 [23]
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 [24]
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, S.N.Y et al. 2020 [26]
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 ionophore. These ionophores allow neutralizing the virus at an early stage of the infection before it can adhere to the host cells and enter it. Rizzo E et al. 2020 [28]
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, F et al. 2020 [29]
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 L et al. 2020 [30]
utilizing modeling approach, predicted lung accumulation of Ivermectin over 10 times higher than EC 50 Arshad et al 2020 [31]
best binding interaction between IVM and RNA-dependent RNA polymerase (RdRp) Swargiary et al.* 2020 [33]
highly efficient binding of IVM to nsp14 Ma et al. 2015 [35]
highly efficient binding of IVM to the viral N phosphoprotein and M protein Eweas et al. 2021 [23]
Level 6: Action on post-translational 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 [23]
Level 7: Action on Karyopherin (KPNA/KPNB) receptors
IVM inhibits the KPNA/KPNB1- mediated nuclear import of viral proteins Caly L et al. 2020 [30]
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 C 2016 [40]
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 X et al. 2008 [42]
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 L et al. 2019 [44]
IVM inhibits lipopolysaccharide (LPS)-induced production of inflammatory cytokines by blocking the NF-κB pathway and improving LPS-induced survival in mice. Zhang X et al. 2008 [42]
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, T., 2020 [39]
STAT-3 induces a C-reactive protein that upregulates PAI-1 levels. Ivermectin inhibits STAT-3. Matsuyama, T., 2020 [39]
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, T., 2020 [39]
Level 12: Action on P21 activated Kinase 1 (PAK-1)
IVM suppresses the Akt/mTOR signaling and promotes ubiquitin-mediated degradation of PAK-1 hence compromising STAT-3 activity and decreasing IL-6 production. Dou Q et al. 2016 [54]
Level 13: Action on Interleukin-6 (IL-6) levels
IVM suppressed IL-6 and TNFα production Zhang X et al. 2008 [42]
IVM “dramatically reduced” IL-6/IL-10 ratio modulating infection outcomes. G D de Melo et al. * 2020 [55]
Level 14: Action on allosteric modulation of P2X4 receptor
Positive allosteric modulation of P2X4 by IVM enhances ATP-mediated secretion of CXCL5 Layhadi JA et al. 2018 [58]
Level 15: Action on high mobility group box 1 (HMGB1)
Ivermectin inhibits HMGB1 Juarez M et al. 2018 [60]
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 G D de Melo et al. * 2020 [55]
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 X et al.,
Ci X et al.,
Yan S et al.
2008
2009
2011
[42, 62, 63]
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 S et al. 2011 [63]
D. ACTION ON OTHER HOST TARGETS
Level 18: Action on Plasmin and Annexin A2
Annexin acts as a co-receptor for the conversion of plasminogen to plasmin in the presence of t-PA. increased levels of plasmin leads to direct activation of STAT-3. Kamber Zaidi et al. 2020 [64]
IVM directly inhibits STAT-3 and could play a role in the inhibition of COVID-19 complications. Matsuyama et al. 2020 [39]
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.
David E.Scheim et al. 2020 [65]
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 H et al. 2017 [67]
  1. *available as preprint; Clinical trials of IVM on COVID-19 available on https://clinicaltrials.gov[7]; Ivermectin for COVID-19: real-time meta-analysis available on https://ivmmeta.com [8]