Project description:Considering the urgency of the ongoing COVID-19 pandemic, detection of new mutant strains and potential re-emergence of novel coronaviruses, repurposing of drugs such as ivermectin could be worthy of attention. This review article aims to discuss the probable mechanisms of action of ivermectin against SARS-CoV-2 by summarizing the available literature over the years. A schematic of the key cellular and biomolecular interactions between ivermectin, host cell, and SARS-CoV-2 in COVID-19 pathogenesis and prevention of complications has been proposed.
Project description: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 have 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 the infection in mammalian cells and human cohort studies. One promising study had reported a marked reduction of 93% of released virion and 99.98% unreleased virion levels upon administration of IVM to Vero-hSLAM cells. IVM's mode of action centres 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 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.
Project description:The well-known anti-helminthic drug ivermectin (IVM) has been established as an example of drug repurposing for the management of SARS-CoV-2 infection. Various study has been done to understand the inhibitory mechanism of IVM against SARS-CoV-2 targets. Broadly, IVM has been categorized as a host-directed agent and the proposed mechanism involves inhibition of the IMPα/ß1-mediated nuclear import of viral proteins. In addition, in vitro/in vivo and molecular docking/dynamic simulation studies suggested multitargets mechanism of IVM against SARS-CoV-2. Present manuscript attempts to provide an overview of the detailed mechanism of action based on experimental and computational studies. The knowledge of binding interaction of IVM and SARS-CoV-2 targets will give the direction to developed new and potential anti-COVID agents. Graphical abstract Image 1
Project description:The recent outbreak of COVID-19 has affected human lives severely. The human-to-human transmission of this viral disease has become deadly due to the unavailability of COVID-19 specific drugs. Here, an overview of various attempts made to design different therapeutic agents against various structural and non-structural proteins of SARS-CoV-2 has been summarized. Emphasis has been made to highlight the mechanisms of drug action and ways to design better inhibitors of these proteins. The roles of anti-oxidants and vitamins in suppressing COVID-19 are also discussed. Graphical abstract Image, graphical abstract
Project description:Predatory publishing represents a major challenge to scholarly communication. This paper maps the infiltration of journals suspected of predatory practices into the citation database Scopus and examines cross-country differences in the propensity of scholars to publish in such journals. Using the names of "potential, possible, or probable" predatory journals and publishers on Beall's lists, we derived the ISSNs of 3,293 journals from Ulrichsweb and searched Scopus with them. 324 of journals that appear both in Beall's lists and Scopus with 164 thousand articles published over 2015-2017 were identified. Analysis of data for 172 countries in 4 fields of research indicates that there is a remarkable heterogeneity. In the most affected countries, including Kazakhstan and Indonesia, around 17% of articles fall into the predatory category, while some other countries have no predatory articles whatsoever. Countries with large research sectors at the medium level of economic development, especially in Asia and North Africa, tend to be most susceptible to predatory publishing. Arab, oil-rich and/or eastern countries also appear to be particularly vulnerable. Policymakers and stakeholders in these and other developing countries need to pay more attention to the quality of research evaluation.Supplementary informationThe online version contains supplementary material available at (10.1007/s11192-020-03852-4).
Project description:The devastating pandemic due to SARS-CoV-2 and the emergence of antigenic variants that jeopardize the efficacy of current vaccines create an urgent need for a comprehensive understanding of the pathophysiology of COVID-19, including the contribution of inflammation to disease. It also warrants for the search of immunomodulatory drugs that could improve disease outcome. Here, we show that standard doses of ivermectin (IVM), an anti-parasitic drug with potential immunomodulatory activities through the cholinergic anti-inflammatory pathway, prevents clinical deterioration, reduces olfactory deficit and limits the inflammation of the upper and lower respiratory tracts in SARS-CoV-2-infected hamsters. Whereas it has no effect on viral load in the airways of infected animals, transcriptomic analyses of infected lungs reveal that IVM dampens type-I interferon responses and modulates several other inflammatory pathways. In particular, IVM dramatically reduces the Il-6/Il-10 ratio in lung tissue and promotes macrophage M2 polarization, which might account for the more favorable clinical presentation of IVM-treated animals. Altogether, this study supports the use of immunomodulatory drugs such as IVM, to improve the clinical condition of SARS-CoV-2-infected patients.
Project description:SARS-CoV-2 is a global threat that influenced healthcare systems around the world. This virus caused an infection in humans with different clinical signs and syndromes, severity, and mortality. The key components of the COVID-19 molecular pathogenesis are coronavirus entry and replication, antigen presentation, humoral and cellular immunity, cytokine storm, coronavirus immune evasion. The analysis of recent literature displayed possible molecular targets in the key components of the COVID-19 pathogenesis. Some of these targets might have gene polymorphisms that influenced the COVID-19 course. Unfortunately, several findings are still putative or extrapolated from SARS and MERS experimental investigations or clinical trials. We systematised original data about gene polymorphisms of possible molecular targets and associations with the COVID-19 course. Most data were obtained for angiotensin-converting enzymes 1 and 2, TMPRSS2 gene polymorphisms. Only a few results were found for gene polymorphisms of adhesion molecules, interferon system components, cytokines, and transcriptional factors, oxidative stress and metabolic molecules, as well as haemocoagulation. Understanding the host gene variability and its associations with COVID-19 can provide insights into the disease pathogenesis, individual susceptibility to SARS-CoV-2 infection, severity, complications, and mortality prognosis for the disease. Besides, these data might help in the identification of appropriate targets for intervention.
Project description:Nucleoside/tide analogues (NAs) have long been used in the fight against viral diseases, and now present a promising option for the treatment of COVID-19. Once activated to the 5'-triphosphate state, NAs act by targeting the viral RNA-dependent RNA-polymerase for incorporation into the viral RNA genome. Incorporated analogues can either 'kill' (terminate) synthesis, or 'corrupt' (genetically or chemically) the RNA. Against coronaviruses, the use of NAs has been further complicated by the presence of a virally encoded exonuclease domain (nsp14) with proofreading and repair capacities. Here, we describe the mechanism of action of four promising anti-COVID-19 NAs; remdesivir, molnupiravir, favipiravir and bemnifosbuvir. Their distinct mechanisms of action best exemplify the concept of 'killers' and 'corruptors'. We review available data regarding their ability to be incorporated and excised, and discuss the specific structural features that dictate their overall potency, toxicity, and mutagenic potential. This should guide the synthesis of novel analogues, lend insight into the potential for resistance mutations, and provide a rational basis for upcoming combinations therapies.
Project description:Despite the huge effort to contain the infection, the novel SARS-CoV-2 coronavirus has rapidly become pandemic, mainly due to its extremely high human-to-human transmission capability, and a surprisingly high viral charge of symptom-less people. While the seek for a vaccine is still ongoing, promising results have been obtained with antiviral compounds. In particular, lactoferrin is regarded to have beneficial effects both in preventing and soothing the infection. Here, we explore the possible molecular mechanisms with which lactoferrin interferes with SARS-CoV-2 cell invasion, preventing attachment and/or entry of the virus. To this aim, we search for possible interactions lactoferrin may have with virus structural proteins and host receptors. Representing the molecular iso-electron surface of proteins in terms of 2D-Zernike descriptors, we 1) identified putative regions on the lactoferrin surface able to bind sialic acid present on the host cell membrane, sheltering the cell from the virus attachment; 2) showed that no significant shape complementarity is present between lactoferrin and the ACE2 receptor, while 3) two high complementarity regions are found on the N- and C-terminal domains of the SARS-CoV-2 spike protein, hinting at a possible competition between lactoferrin and ACE2 for the binding to the spike protein.
Project description:On March 11, 2020, the World Health Organization (WHO) declared the severe acute respiratory syndrome caused by coronavirus 2 (SARS-CoV-2) a global pandemic. As of July 2020, SARS-CoV-2 has infected more than 14 million people and provoked more than 590,000 deaths, worldwide. From the beginning, a variety of pharmacological treatments has been empirically used to cope with the life-threatening complications associated with Corona Virus Disease 2019 (COVID-19). Thus far, only a couple of them and not consistently across reports have been shown to further decrease mortality, respect to what can be achieved with supportive care. In most cases, and due to the urgency imposed by the number and severity of the patients' clinical conditions, the choice of treatment has been limited to repurposed drugs, approved for other indications, or investigational agents used for other viral infections often rendered available on a compassionate-use basis. The rationale for drug selection was mainly, though not exclusively, based either i) on the activity against other coronaviruses or RNA viruses in order to potentially hamper viral entry and replication in the epithelial cells of the airways, and/or ii) on the ability to modulate the excessive inflammatory reaction deriving from dysregulated host immune responses against the SARS-CoV-2. In several months, an exceptionally large number of clinical trials have been designed to evaluate the safety and efficacy of anti-COVID-19 therapies in different clinical settings (treatment or pre- and post-exposure prophylaxis) and levels of disease severity, but only few of them have been completed so far. This review focuses on the molecular mechanisms of action that have provided the scientific rationale for the empirical use and evaluation in clinical trials of structurally different and often functionally unrelated drugs during the SARS-CoV-2 pandemic.