Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo

Lv, Changjie; Liu, Wenkai; Wang, Bin; Dang, Ruyi; Qiu, Li; Ren, Juan; Yan, C X; Yang, Zhicong; Wang, Xinglong

doi:10.1016/j.antiviral.2018.09.010

Cited by 105 publications

(96 citation statements)

References 32 publications

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“…Importantly, it has been demonstrated to limit infection by RNA viruses such as DENV 1-4 (Tay et al, 2013), West Nile Virus (Yang et al, 2020), Venezuelan equine encephalitis virus (VEEV) (Lundberg et al, 2013) and influenza (Gotz et al, 2016), with this broad spectrum activity believed to be due to the reliance by many different RNA viruses on IMPα/β1 during infection (Caly et al, 2012;Jans et al, 2019). Ivermectin has similarly been shown to be effective against the DNA virus pseudorabies virus (PRV) both in vitro and in vivo, with ivermectin treatment shown to increase survival in PRV-infected mice (Lv et al, 2018). Efficacy was not observed for ivermectin against Zika virus (ZIKV) in mice, but the authors acknowledged that study limitations justified re-evaluation of ivermectin's anti-ZIKV activity (Ketkar et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro

et al. 2020

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Section: Introductionmentioning

confidence: 99%

The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro

et al. 2020

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“…The list of RNA viruses include Human immune-deficiency virus, dengue virus [10], West Nile Virus [11], Venezuelan equine encephalitis virus [12], influenza virus [13] and yellow fever virus [14]. Inhibitory activity has also been shown against DNA viruses-Simian virus SV40 and pseudorabies virus [10,15]. Amidst the present global crisis struggling with the pandemic, Australian researchers, Caly et al, successfully demonstrated inhibitory activity of the drug in SARS-Cov-2 virus transfected cell lines.…”

Section: In Vitro Evidence Of Anti-viral Activitymentioning

confidence: 99%

“…The mechanism of antiviral activity in DNA virus is also by inhibition of cytoplasm to nucleus transport of NCP. In cell lines transfected with pseudorabies virus, ivermectin was shown to disrupt the nuclear localization of UL42 NCP by targeting the nuclear localization signal of the protein [15].…”

Section: Mechanism Of Antiviral Actionmentioning

confidence: 99%

“…The authors found that use of higher dose to achieve the therapeutic concentration predicted by the in vitro experiment proved too toxic for the control group leaving no scope for further investigation [18]. Conversely, in a murine model of pseudo rabies virus infection, ivermectin treatment increased the survival rates of infected mice and also decreased infection severity and gross intracranial lesions [15]. In a rather interesting and unique study involving induced Dengue virus infection in Aedes albopictus mosquitoes, ivermectin fed mosquitoes were found to have significantly lower rate of infection as well as decreased tissue viral load [19].…”

Section: Evidence In Animal Modelsmentioning

confidence: 99%

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The Battle against COVID 19 Pandemic: What we Need to Know Before we “Test Fire” Ivermectin

et al. 2020

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The world is faced with the dire challenge of finding an effective treatment against the rampaging COVID 19 pandemic. Amidst the crisis, reports of in vitro inhibitory activity of ivermectin, an approved anthelmintic, against the causative SARSCoV2 virus, have generated lot of optimism. In this article, we have fished and compiled the needed information on the drug, that will help readers and prospective investigators in having a quick overview. Though the primordial biological action of the drug is allosteric modulation of helminthic ion channel receptor, its in vitro activity against both RNA and DNA viruses is known for almost a decade. In the past two years, efficacy study in animal models of pseudorabies and zika virus was found to be favourable and unfavourable respectively. Only one clinical study evaluated the drug in dengue virus infection without any clinical efficacy. However, the proposed mechanism of drug action, by inhibiting the importin family of nucleus-cytoplasmic transporters along with favourable pharmacokinetics, warrants exploration of its role in COVID 19 through safely conducted clinical trials. Being an available and affordable drug, enlisted in WHO List of Essential Medicine, and a long track record of clinical safety, the drug is already in clinical trials the world over. As the pandemic continues to ravage human civilisation with unabated intensity, the world eagerly waits for a ray of hope emanating from the outcome of the ongoing trials with ivermectin as well as other drugs.

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“…It causes stimulation of gamma amino-butyric acid (GABA)-gated-Cl-channels, leading to hyperpolarization, and resulting in paralysis of helminth parasites (Canga et al 2008). Furthermore, ivermectin is also known to act as inhibitor of importin-α/β-mediated nuclear import and suppress the replication of several RNA viruses, including HIV, chikungunya virus, and yellow fever virus (Lv et al 2018). Recent studies have shown that ivermectin can inhibit the replication of SARS-CoV-2 in vitro (Sharun et al 2020).…”

Section: Introductionmentioning

confidence: 99%

Ivermectin as a promising RNA-dependent RNA polymerase inhibitor and a therapeutic drug against SARS-CoV2: Evidence from in silico studies

Swargiary

2020

Preprint

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Purpose: COVID-19, caused by SARS-CoV2 virus is a contagious disease affecting millions of lives throughout the globe. Currently, there are no clinically approved drugs for SARS-CoV2 although some drugs are undergoing clinical trials. The present study investigates the binding property of ivermectin on four important drug targets, spike protein, RNA-dependent RNA polymerase, 3-chymotrypsin- and papain-like proteases of SARS-CoV2. Methods: The 3D structure of ivermectin along with known antiviral drug lopinavir, simeprevir and four nucleotides ATP, GTP, CTP, and UTP were downloaded from PubChem database. Crystal structures of proteins were downloaded from PDB database. PDB files were converted into pdbqt file using AutoDock tools. After proper processing and grid formation, docking was carried out in AutoDock vina. Furthermore, the co-crystallized RNA and its binding interactions with RdRp were studied using various visualization tools including Discovery studio.Results: Docking study showed that ivermectin is the best binding drug compared to lopinavir and simeprevir. The best binding interaction was found to be -9.7kcal/mol with RdRp suggesting potential inhibitor of the protein. Twenty-one amino acid residues of RdRp were found to interact with ivermectin including the catalytic residue Asp760. Furthermore, RNA-RdRp complex revealed that the catalytic active residues Ser759 and Asp760 of RdRp formed strong interactions with RNA chain. Binding of ivermectin in the active site of RdRp make clash with the nucleotides of RNA chain suggesting the possible inhibition of replication.Conclusions: The present study suggests ivermectin as a potential inhibitor of RdRp which may be crucial to combat the SARS-CoV2.

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Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo

Cited by 105 publications

References 32 publications

The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro

The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro

The Battle against COVID 19 Pandemic: What we Need to Know Before we “Test Fire” Ivermectin

Ivermectin as a promising RNA-dependent RNA polymerase inhibitor and a therapeutic drug against SARS-CoV2: Evidence from in silico studies

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