Repositioning Ivermectin for Covid-19 treatment: Molecular mechanisms of action...
- Tushar Savaliya
- Oct 23, 2021
- 10 min read
Repositioning Ivermectin for Covid-19 treatment: Molecular mechanisms of action against SARS-CoV-2 replication
Abstract
Ivermectin (IVM) is an FDA-approved macrocyclic lactone compound traditionally used to treat parasitic infestations and has shown to have antiviral potential from previous in-vitro studies. Currently, IVM is commercially available as a veterinary drug but has also been applied in humans to treat onchocerciasis (river blindness - a parasitic worm infection) and strongyloidiasis (a roundworm/nematode infection). In light of the recent pandemic, the repurposing of IVM to combat SARS-CoV-2 has acquired significant attention. Recently, IVM has been proven effective in numerous in-silico and molecular biology experiments against infection in mammalian cells and human cohort studies. One promising study had reported a marked reduction of 93% of the released virion and 99.98% unreleased virion levels upon administration of IVM to Vero-hSLAM cells. IVM's mode of action centers around the inhibition of the cytoplasmic-nuclear shuttling of viral proteins by disrupting the Importin heterodimer complex (IMPα/β1) and downregulating STAT3, thereby effectively reducing the cytokine storm. Furthermore, the ability of IVM to block the active sites of viral 3CLpro and S protein disrupts important machinery such as viral replication and attachment. This review compiles all the molecular evidence to date, in the review of the antiviral characteristics exhibited by IVM. Thereafter, we discuss IVM's mechanism and highlight the clinical advantages that could potentially contribute towards disabling the viral replication of SARS-CoV-2. In summary, the collective review of recent efforts suggests that IVM has a prophylactic effect and would be a strong candidate for clinical trials to treat SARS-CoV-2.
1. Introduction
The recent pandemic of Covid-19 has been acknowledged as a global health crisis that has threatened public health and safety. This phenomenon has raised awareness and conflict towards the healthcare sector for their negligence and absence of alternative measures that would have prevented or successfully treated novel causative viral agents. Approximately 233,000,000 individuals have been affected during this pandemic, and 4,750,000 associated deaths were correlated worldwide. Currently, the cases of Covid-19 are still growing rapidly on a global scale [1]. The etiological agent that contributed to this disastrous episode is known to be the SARS Coronavirus – 2 (SARS-CoV-2). To date, the origin of SARS-CoV-2 is still debated though evidence suggests bats as the source of the virus, akin to the SARS-CoV outbreak identified during 2002 [2]. Although SARS-CoV-2 carries a 3.4% mortality rate, which is significantly lower than its predecessors (SARS-CoV and MERS-CoV), it is more infectious. Of note, up to 15% of SARS-CoV-2 cases led to several critical complications such as pneumonia, heart arrhythmia, septic shock, multiple organ failure, and the more pronounced acute respiratory distress syndrome (ARDS) [3]. Thus, emphasizing the need for effective antiviral therapy. In this urgent time of need, drug repositioning attempts are crucial to address the immediate demand for a fast and effective antiviral therapy against COVID-19. Drug repositioning, also known as drug repurposing or drug recycling, is an alternative approach to finding new use of an established drug to treat other diseases aside from the intended ones. A repositioned drug has often gone through all the rigorous safety and pharmacokinetic profiling studies with well-established ADMET (absorption, distribution, metabolism, excretion, toxicity) data [4]. The benefits of utilizing repositioned drugs are the omission of critical and time-consuming drug development stages, which significantly reduces the time needed to produce an effective antiviral drug. In this paradigm, we discuss the numerous drug candidates already proposed for SARS-CoV-2 treatment, such as Remdesivir, Lopinavir-Ritonavir, Oseltamivir, Saquinavir, Tenofovir, and ciclesonide [5]. Firstly, Lopinavir-Ritonavir and Saquinavir have been proven effective in inhibiting the replication of SARS-CoV-2 via forming a stable complex with its main protease (Mopar or 3CLpro), which oversees the regulation of replicase polyprotein proteolytic activity and viral replication [6], [7]. Conversely, tenofovir as a nucleotide analog for HIV treatment was revealed to interact with papain-like protease (PLpro) and Mopar. This interferes with the binding of SARS-CoV-2 S protein to the host ACE2 receptor, subsequently reducing the production of non-structural protein (NSP) required for viral replication [8]. Additionally, tenofovir also binds to SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), an important replicase for viral replication, effectively bringing down the viral load [8]. Ciclesonide is a corticosteroid was reported to have targeted the nsp15 or also known as the Indo viral RNA endoribonuclease uridylate-specific (NendoU) enzyme in SARS-CoV-2. This protein interferes with the human innate immune response, contributing to its immune-evasive properties in COVID-19 patients [9].
2. Antiparasitic action of Ivermectin
As aforementioned, IVM was chemically derived from AVMs, a group of 16-membered macrocyclic lactone compounds. IVM possesses two variants as A or B, which are differentiated by the presence of methoxy or hydroxyl groups at C5, respectively. AVMs naturally occur as mixtures of eight compounds A1a, A1b, A2a, A2b, B1a, B1b, B2a and B2b, from which, B1 is administered orally while B2 is parenterally administered [23]. The subscript ‘1’ following the variants indicates the presence of double bonds between C22 and C23 whereas, the subscript of ‘2’ describes the presence of hydrogen and hydroxyl groups at C22 and C23, respectively [23]. As such, IVM is a semi-synthetic derivative of Avermectin B1 where it consists of two homologues, 22, 23-dihydro-avermectin B1a and 22, 23-dihydro-avermectin B1b in the ratio of 80:20 [24]. IVM is capable of affecting the motility, feeding, and reproduction of parasites through high-affinity binding to the γ-aminobutyric acid (GABA)-regulated or glutamate-gated chloride channels. In response, the activities of these channels are enhanced, leading to hyperpolarization of the cell membrane and influx of chloride ions. Subsequently, this inhibits the regulatory light chain of myosin II phosphorylation via p21 activated kinase 1 (PAK1), causing muscle paralysis and eventually, parasite death [25]. Apart from its original function, IVM has been proven effective in numerous antiviral treatments via the inhibition of the nuclear import of viral nucleoproteins. This encompasses HIV-1, West Nile Virus (WNV), tick-borne encephalitis, Zika Virus (ZKV), Venezuelan equine encephalitis virus, Chikungunya virus, Pseudorabies virus, Adenovirus, Influenza virus, SARS-CoV-1, and most recently in SARS-CoV-2 [26], [27], [28]. The mode of inhibition of the aforementioned viruses were described in detail below.
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