Ivermectin as a Broad-Spectrum Host-Directed Antiviral: The Real Deal?

Jans, David A.; Wagstaff, Kylie M.

doi:10.3390/cells9092100

Cited by 69 publications

(69 citation statements)

References 50 publications

(152 reference statements)

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“…On this regard, the in vivo mouse model of MHV infection would not support a modulatory action of ivermectin on the immune response. On the other hand, these results are in accordance with various reports demonstrating that the broad-spectrum antiviral potential of ivermectin against several RNA viruses is due to its ability to specifically bind to and destabilize the importin α/β heterodimer, thereby preventing importin α/β from binding to the viral protein, which in turn blocks the nuclear trafficking of viral proteins (Jans and Wagstaff, 2020;Sharun et al, 2020;Caly et al, 2020).…”

Section: Discussionsupporting

confidence: 92%

Ivermectin reduces coronavirus infectionin vivo: a mouse experimental model

Arevalo

Pagotto

Pórfido

et al. 2020

Preprint

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SARS-CoV2 is a single strand RNA virus member of the type 2 coronavirus family, responsible for causing COVID-19 disease in humans. The objective of this study was to test the ivermectin drug in a murine model of coronavirus infection using a type 2 family RNA coronavirus similar to SARS-CoV2, the mouse hepatitis virus (MHV). BALB/cJ female mice were infected with 6,000 PFU of MHV-A59 (Group Infected; n=20) and immediately treated with one single dose of 500 ug/kg of ivermectin (Group Infected + IVM; n=20), or were not infected and treated with PBS (Control group; n=16). Five days after infection/treatment, mice were euthanized to obtain different tissues to check general health status and infection levels. Overall results demonstrated that viral infection induces the typical MHV disease in infected animals, with livers showing severe hepatocellular necrosis surrounded by a severe lymphoplasmacytic inflammatory infiltration associated with a high hepatic viral load (52,158 AU), while ivermectin administration showed a better health status with lower viral load (23,192 AU; p<0.05) and few livers with histopathological damage (p<0.05), not showing statistical differences with control mice (P=NS). Furthermore, serum transaminase levels (aspartate aminotransferase and alanine aminotransferase) were significantly lower in treated mice compared to infected animals. In conclusion, ivermectin seems to be effective to diminish MHV viral load and disease in mice, being a useful model for further understanding new therapies against coronavirus diseases.

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Section: Discussionsupporting

confidence: 92%

Ivermectin reduces coronavirus infectionin vivo: a mouse experimental model

Arevalo

Pagotto

Pórfido

et al. 2020

Preprint

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“…IVM is an approved drug for treatment of rosacea due to its antiparasitic properties complemented by anti-inflammatory activity [10][11][12]. In addition, the activity of IVM against various viruses [13], including COVID-19 [14,15], is of a special interest. Several clinical studies are planned or have been started for this indication [16,17].…”

Section: Introductionmentioning

confidence: 99%

Crystal Structures of New Ivermectin Pseudopolymorphs

2021

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New pseudopolymorphs of ivermectin (IVM), a potential anti-COVID-19 drug, were prepared. The crystal structure for three pseudopolymorphic crystalline forms of IVM has been determined using single-crystal X-ray crystallographic analysis. The molecular conformation of IVM in crystals has been compared with the conformation of isolated molecules modeled by DFT calculations. In a solvent with relatively small molecules (ethanol), IVM forms monoclinic crystal structure (space group I2), which contains two types of voids. When crystallized from solvents with larger molecules, like -valerolactone (GVL) and methyl tert-butyl ether (MTBE), IVM forms orthorhombic crystal structure (space group P212121). Calculations of the lattice energy indicate that interactions between IVM and solvents play a minor role; the main contribution to energy is made by the interactions between the molecules of IVM itself, which form a framework in the crystal structure. Interactions between IVM and molecules of solvents were evaluated using Hirshfeld surface analysis. Thermal analysis of the new pseudopolymorphs of IVM was performed by differential scanning calorimetry and thermogravimetric analysis.

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“…Additional studies have been reporting the broad-spectrum anti-parasitic drug ivermectin as a SARS-CoV-2 replication inhibitor (Caly et al, 2020), since other studies have reported many antiviral actions against HIV (Wagstaff et al, 2012;Caly et al, 2020;Heidary and Gharebaghi, 2020), DENV (Xu et al, 2018;Caly et al, 2020;Heidary and Gharebaghi, 2020), ZIKA (Caly et al, 2020;Heidary and Gharebaghi, 2020), and Influenza A (Götz et al, 2016;Heidary and Gharebaghi, 2020). This drug is a macrocyclic lactone with its main antiviral mechanism of action in the nuclear transport role of the host importin α (IMPα) protein (Jans and Wagstaff, 2020;Schwemmle et al, 2020). Furthermore, one study has showed that this molecule presented antiviral effects against the SARS-CoV-2 in vitro assays with Vero/ hSLAM cells with 5000-fold reduction in viral RNA after 48 h with IC50 varying from 2.2 to 2.5 μM (Caly et al, 2020;Sharun et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Repurposing Approved Drugs for Guiding COVID-19 Prophylaxis: A Systematic Review

et al. 2020

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The SARS-CoV-2 outbreak originally appeared in China in December 2019 and became a global pandemic in March 2020. This infectious disease has directly affected public health and the world economy. Several palliative therapeutic treatments and prophylaxis strategies have been used to control the progress of this viral infection, including pre-(PrEP) and post-exposure prophylaxis. On the other hand, research groups around the world are still studying novel drug prophylaxis and treatment using repurposing approaches, as well as vaccination options, which are in different pre-clinical and clinical testing phases. This systematic review evaluated 1,228 articles from the PubMed and Scopus indexing databases, following the Kitchenham bibliographic searching protocol, with the aim to list drug candidates, potentially approved to be used as new options for SARS-CoV-2 prophylaxis clinical trials and medical protocols. In searching protocol, we used the following keywords: “Covid-19 or SARS-CoV-2” or “Coronavirus or 2019 nCoV,” “prophylaxis,” “prophylactic,” “pre-exposure,” “COVID-19 or SARS-CoV-2 Chemoprophylaxis,” “repurposed,” “strategies,” “clinical,” “trials,” “anti-SARS-CoV-2,” “anti-covid-19,” “Antiviral,” “Therapy prevention in vitro,” in cells “and” human testing. After all protocol steps, we selected 60 articles that included: 15 studies with clinical data, 22 studies that used in vitro experiments, seven studies using animal models, and 18 studies performed with in silico experiments. Additionally, we included more 22 compounds between FDA approved drugs and drug-like like molecules, which were tested in large-scale screenings, as well as those repurposed approved drugs with new mechanism of actions. The drugs selected in this review can assist clinical studies and medical guidelines on the rational repurposing of known antiviral drugs for COVID-19 prophylaxis.

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Ivermectin as a Broad-Spectrum Host-Directed Antiviral: The Real Deal?

Cited by 69 publications

References 50 publications

Ivermectin reduces coronavirus infectionin vivo: a mouse experimental model

Ivermectin reduces coronavirus infectionin vivo: a mouse experimental model

Crystal Structures of New Ivermectin Pseudopolymorphs

Repurposing Approved Drugs for Guiding COVID-19 Prophylaxis: A Systematic Review

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