The recent report by Caly et al., describing the antiviral potential of ivermectin
against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro
arrive to the agenda of potential candidates for COVID-19 treatment . This discovery
gave hope to the researchers who are screening for drugs that can be repurposed for
treating the Coronavirus Disease 2019 (COVID-19). Ivermectin, is a member of the avermectin
family (Fig. 1); as these compounds are produced by the soil microorganism, Streptomyces
avermitilis, they are called avermectins . Ivermectin has showed a wide range of
activities, ranging from broad-spectrum endo/ecto-parasiticide activity to antiviral,
antibacterial, and anticancer activities . It was first introduced commercially
in 1981 for use in animals. In addition to being used for treating billions of livestock
and companion animals worldwide to help maintain food production and animal health,
ivermectin is also used for treating several diseases in humans, e.g. a key drug in
the elimination programs of onchocercosis [3, 4]. Ivermectin is considered a drug
of choice for various parasitic diseases. As an anthelmintic drug, its mechanism of
action in invertebrates mainly involves the opening of glutamate-gated and Gamma aminobutyric
acid (GABA)-gated chloride channels, leading to increased conductance of chloride
ions and causing subsequent motor paralysis in parasites .
Chemical structure of ivermectin, the 22, 23-dihydro derivative of a macrocyclic lactone
This is not the first time that ivermectin has exhibited antiviral potential against
human and animal viruses. The first report on the in vivo effectiveness of ivermectin
against viruses demonstrated its effect against parvoviruses in a freshwater crayfish
(Cherax quadricarinatus) model . This broad-spectrum endo/ecto-parasiticide has
exhibited potent antiviral effects against several ribonucleic acid (RNA) viruses,
such as Zika virus , influenza A virus , Venezuelan equine encephalitis virus
, West Nile virus , porcine reproductive and respiratory syndrome virus ,
Newcastle disease virus , chikungunya virus , human immunodeficiency virus
(HIV-1) , yellow fever virus, dengue virus, Japanese encephalitis virus, and tick-borne
encephalitis virus . However, the in vivo antiviral potential of ivermectin has
only been reported against the West Nile virus  and Newcastle disease virus .
It has been demonstrated that ivermectin showed strong antiviral activity against
Newcastle disease virus at a concentration of 100 μg/ml, and exerted cytotoxicity
in primary chick fibroblast cells . Ivermectin has also exhibited antiviral activity
against deoxyribonucleic acid (DNA) viruses, such as the pseudorabies virus ,
porcine circovirus 2 , parvoviruses , and bovine herpesvirus 1 . However,
the in vivo antiviral potential of ivermectin has only been reported against the pseudorabies
virus  and parvoviruses .
In the study by Caly et al., Vero-hSLAM cells were treated with ivermectin after 2
h of SARS-CoV-2 infection, resulting in ~5000-fold reduction in viral RNA after 48 h
. Although the positive result obtained in the in vitro studies suggests the possible
in vivo antiviral potential of ivermectin, further validation using an efficient in
vivo model is still required. As a matter of concern, we should also consider our
previous experience with the in vivo antiviral potential of ivermectin against the
Zika virus. Even though its antiviral activity was proven in vitro , ivermectin
was ineffective at preventing lethal Zika virus (Senegal strain) infection in Ifnar1-knockout
mice . Even though ivermectin has exhibited antiviral activity against several
RNA viruses in vitro, further studies in in vivo models have been conducted against
only a few of these viruses [10, 12].
Ivermectin was previously found to inhibit flavivirus replication by specifically
targeting the activity of non-structural 3 helicase (NS3 helicase) in vitro. It is
a potent inhibitor of the yellow fever virus and a weak inhibitor of other flaviviruses,
such as Japanese encephalitis, dengue, and tick-borne encephalitis viruses . Ivermectin
was also found to inhibit the nuclear accumulation of HIV-1 integrase and the non-structural
protein 5 (NS5) polymerase of the dengue virus, a phenomenon that is dependent on
importin α/β nuclear transport . The broad-spectrum antiviral potential of ivermectin
against several RNA viruses is due to its ability to specifically inhibit importin
α/β-mediated nuclear transport, which in turn blocks the nuclear trafficking of viral
proteins . Several RNA viruses depend on Impα/β1 during the process of infection
. SARS-CoV-2, is an RNA virus, is expected to show a similar mechanism of action.
The proposed anti-SARS-CoV-2 action of ivermectin involves the binding of ivermectin
to the Impα/β1 heterodimer, leading to its destabilization and prevention of Impα/β1binding
to the viral proteins. This prevents viral proteins from entering the nucleus, thereby
reducing the inhibition of antiviral responses and leading to an efficient antiviral
The antiviral activity of ivermectin is also found to be related to other mechanisms.
Ivermectin has been reported to suppress the replication of the pseudorabies virus
by inhibiting the nuclear import of UL42 (an accessory subunit of DNA polymerase)
. A similar mechanism of inhibition was reported for another DNA virus, bovine
herpesvirus 1 . Ivermectin inhibits the nuclear localization signal-mediated import
of capsid protein (Cap) of porcine circovirus 2 . It is, therefore, necessary
to identify the exact mechanism underlying the in vitro antiviral activity of ivermectin
against SARS-CoV-2 to obtain an insight into the possible mechanism of infection.
An overview of the potential modes of the antiviral action of ivermectin is presented
in Fig. 2.
Potential modes of anti-viral actions of ivermectin
It has also been hypothesized that combination therapy using hydroxychloroquine and
ivermectin may exert a synergistic inhibitory effect on SARS-CoV-2. In this combination,
hydroxychloroquine acts by inhibiting the entry of SARS-CoV-2 into the host cells,
whereas ivermectin further enhances the antiviral activity by inhibiting viral replication
. Considering the promising result of the in vitro study, the clinical benefit
of ivermectin therapy was evaluated in an observational registry-based study involving
critically ill SARS-CoV-2-infected patients. Treatment with ivermectin at a dose of
150 μg/kg was found to be associated with a lower mortality rate and reduced healthcare
resource use . Even though the result of this preliminary study provides hope
for the utilization of ivermectin in a clinical setting, further evaluation in randomized
clinical control trials is required before this wonder drug can be adapted into treatment
guidelines, as has been occurring with other drugs under use and investigation in
COVID-19, such as chloroquine .
Besides, although ivermectin has been reported to exert potent antiviral activity
against many viruses, its application is mainly hampered by pharmacokinetic problems
such as high cytotoxicity and low solubility. To overcome these problems, various
liposomal systems have been engineered and used as ivermectin nanocarriers in several
cell lines, which resulted in lower cytotoxicity than that of free ivermectin .
Before considering ivermectin for widespread use as an antiviral agent, detailed in
vivo and in vitro investigations of its effect in various animal models and cell culture
systems are of utmost importance.
The in vitro antiviral activity of ivermectin against SARS-CoV-2 has further extended
the antiviral spectrum of this drug. As ivermectin is an United States Food and Drug
Administration (FDA)-approved drug, repurposing it for anti-SARS-CoV-2 therapy will
not be a problem. Nevertheless, the real question is, will it reach the stage of randomized
clinical control trials in SARS-CoV-2-infected patients, or will it fail in the in
vivo study stage? Although no clinical trials have reported its efficacy and safety
in the context of COVID-19 yet, is expected to see in the near future them, delivering
information about its potential therapeutic action in the clinical setting.
Hence, we can conclude the following:
Ivermectin exerts broad-spectrum antiviral activity against several animal and human
viruses, including both RNA and DNA viruses.
The antiviral potential of ivermectin against various viruses is mediated via the
targeting of the following: importin α/β-mediated nuclear transport of HIV-1 integrase
and NS5 polymerase; NS3 helicase; nuclear import of UL42; and nuclear localization
signal-mediated nuclear import of Cap.
As SARS-CoV-2 is an RNA virus, the antiviral activity of ivermectin may be mediated
through the inhibition of importin α/β-mediated nuclear transport of viral proteins.
The clinical efficacy and utility of ivermectin in SARS-CoV-2-infected patients are
unpredictable at this stage, as we are dealing with a completely novel virus.