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1.
Fundam Clin Pharmacol ; 35(2): 260-276, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1020589

ABSTRACT

Viral infections remain a major cause of economic loss with an unmet need for novel therapeutic agents. Ivermectin is a putative antiviral compound; the proposed mechanism is the inhibition of nuclear translocation of viral proteins, facilitated by mammalian host importins, a necessary process for propagation of infections. We systematically reviewed the evidence for the applicability of ivermectin against viral infections including SARS-CoV-2 regarding efficacy, mechanisms and selective toxicity. The SARS-CoV-2 genome was mined to determine potential nuclear location signals for ivermectin and meta-analyses for in vivo studies included all comparators over time, dose range and viral replication in multiple organs. Ivermectin inhibited the replication of many viruses including those in Flaviviridae, Circoviridae and Coronaviridae families in vitro. Real and mock nuclear location signals were identified in SARS-CoV-2, a potential target for ivermectin and predicting a sequestration bait for importin ß, stopping infected cells from reaching a virus-resistant state. While pharmacokinetic evaluations indicate that ivermectin could be toxic if applied based on in vitro studies, inhibition of viral replication in vivo was shown for Porcine circovirus in piglets and Suid herpesvirus in mice. Overall standardized mean differences and 95% confidence intervals for ivermectin versus controls were -4.43 (-5.81, -3.04), p < 0.00001. Based on current results, the potential for repurposing ivermectin as an antiviral agent is promising. However, further work is needed to reconcile in vitro studies with clinical efficacy. Developing ivermectin as an additional antiviral agent should be pursued with an emphasis on pre-clinical trials in validated models of infection.


Subject(s)
Anthelmintics/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Ivermectin/pharmacology , SARS-CoV-2/drug effects , Animals , Anthelmintics/therapeutic use , Antiviral Agents/therapeutic use , Computer Simulation , Drug Repositioning , Humans , Ivermectin/therapeutic use , Swine
2.
ACS Pharmacol Transl Sci ; 3(6): 1371-1380, 2020 Dec 11.
Article in English | MEDLINE | ID: covidwho-983811

ABSTRACT

There is urgent therapeutic need for COVID-19, a disease for which there are currently no widely effective approved treatments and the emergency use authorized drugs do not result in significant and widespread patient improvement. The food and drug administration-approved drug ivermectin has long been shown to be both antihelmintic agent and a potent inhibitor of viruses such as Yellow Fever Virus. In this study, we highlight the potential of ivermectin packaged in an orally administrable nanoparticle that could serve as a vehicle to deliver a more potent therapeutic antiviral dose and demonstrate its efficacy to decrease expression of viral spike protein and its receptor angiotensin-converting enzyme 2 (ACE2), both of which are keys to lowering disease transmission rates. We also report that the targeted nanoparticle delivered ivermectin is able to inhibit the nuclear transport activities mediated through proteins such as importin α/ß1 heterodimer as a possible mechanism of action. This study sheds light on ivermectin-loaded, orally administrable, biodegradable nanoparticles to be a potential treatment option for the novel coronavirus through a multilevel inhibition. As both ACE2 targeting and the presence of spike protein are features shared among this class of virus, this platform technology has the potential to serve as a therapeutic tool not only for COVID-19 but for other coronavirus strains as well.

3.
J Cell Physiol ; 236(4): 2959-2975, 2021 04.
Article in English | MEDLINE | ID: covidwho-777472

ABSTRACT

Viruses such as human cytomegalovirus (HCMV), human papillomavirus (HPV), Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), and coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) represent a great burden to human health worldwide. FDA-approved anti-parasite drug ivermectin is also an antibacterial, antiviral, and anticancer agent, which offers more potentiality to improve global public health, and it can effectively inhibit the replication of SARS-CoV-2 in vitro. This study sought to identify ivermectin-related virus infection pathway alterations in human ovarian cancer cells. Stable isotope labeling by amino acids in cell culture (SILAC) quantitative proteomics was used to analyze human ovarian cancer cells TOV-21G treated with and without ivermectin (20 µmol/L) for 24 h, which identified 4447 ivermectin-related proteins in ovarian cancer cells. Pathway network analysis revealed four statistically significant antiviral pathways, including HCMV, HPV, EBV, and HIV1 infection pathways. Interestingly, compared with the reported 284 SARS-CoV-2/COVID-19-related genes from GencLip3, we identified 52 SARS-CoV-2/COVID-19-related protein alterations when treated with and without ivermectin. Protein-protein network (PPI) was constructed based on the interactions between 284 SARS-CoV-2/COVID-19-related genes and between 52 SARS-CoV-2/COVID-19-related proteins regulated by ivermectin. Molecular complex detection analysis of PPI network identified three hub modules, including cytokines and growth factor family, MAP kinase and G-protein family, and HLA class proteins. Gene Ontology analysis revealed 10 statistically significant cellular components, 13 molecular functions, and 11 biological processes. These findings demonstrate the broad-spectrum antiviral property of ivermectin benefiting for COVID-19 treatment in the context of predictive, preventive, and personalized medicine in virus-related diseases.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Ivermectin/pharmacology , Cell Line, Tumor , Humans , Proteomics/methods , SARS-CoV-2
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