Dual action anti-inflammatory/antiviral isoquinoline alkaloids as potent naturally occurring anti-SARS-CoV-2 agents: A combined pharmacological and medicinal chemistry perspective.

In the search for compounds that inhibit the SARS-CoV-2 after the onset of the COVID-19 pandemic, isoquinoline-containing alkaloids have been identified as compounds with high potential to fight the disease. In addition to having strong antiviral activities, most of these alkaloids have significant anti-inflammatory effects which are often manifested through the inhibition of a promising host-based anti-COVID-19 target, the p38 MAPK signaling pathway. In the present review, our pharmacological and medicinal chemistry evaluation resulted in highlighting the potential of anti-SARS-CoV-2 isoquinoline-based alkaloids for the treatment of COVID-19 patients. Considering critical parameters of the antiviral and anti-inflammatory activities, mechanism of action, as well as toxicity/safety profile, we introduce the alkaloids emetine, cephaeline, and papaverine as high-potential therapeutic agents for use in the treatment of COVID-19. Although preclinical studies confirm that some isoquinoline-based alkaloids reviewed in this study have a high potential to inhibit the SARS-CoV-2, their entry into drug regimens of COVID-19 patients requires further clinical trial studies and toxicity evaluation.

Phytomedicines for Covid-19: Opportunities and Obstacles

COVID-19 is a disease caused by SARS-CoV-2 that can trigger respiratory tract infection. Due to its tendency to affect the upper respiratory tract (sinuses, nose and throat) or lower respiratory tract (windpipe and lungs), this disease is life-threatening and affects a large number of populations. This virus's unique and complex nature enhances the scope to look into the direction of herbal plants and their constituents for its prevention and treatment. The herbal remedies can have preventive as well as therapeutic actions. This review focuses on various aspects of using herbal medicines for COVID-19, as herbal constituents may also have adverse effects. Various studies revealed that some medicinal plants show life-threatening adverse effects, so selecting plants, and their related studies should be appropriate and strategic. This article includes various factors that should be considered before herbal drug use in COVID-19 patients. These are clinical trials, safety, molecular mechanism, and self-medication, which have been elaborated. This article also discusses the targets of covid-19 and different coronavirus strains. As before, treatment diagnosis of the disease is very important. Various patents have been filed and granted for its proper diagnosis so that its treatment can be easy.Copyright © 2022 Society of Pharmaceutical Sciences and Research. All rights reserved.

Emetine, a potent alkaloid for the treatment of SARS-CoV-2 targeting papain-like protease and non-structural proteins: pharmacokinetics, molecular docking and dynamic studies.

The main objective of this study is to find out the anti-SARS-CoV-2 potential of emetine by using molecular docking and dynamic simulation approaches. Interestingly, molecular docking studies suggest that Emetine showed significant binding affinity toward Nsp15 (-10.8 kcal/mol) followed by Nsp12 (-9.5 kcal/mol), RNA-dependent RNA polymerase, RdRp (-9.5 kcal/mol), Nsp16 (-9.4 kcal/mol), Nsp10 (-9.2 kcal/mol), Papain-like protein (-9.0 kcal/mol), Nsp13 (-9.0 kcal/mol), Nsp14 (-8.9 kcal/mol) and Spike Protein Receptor Domain (-8.8 kcal/mol) and chymotrypsin-like protease, 3CLpro (-8.5 kcal/mol), respectively, which are essential for viral infection and replication. In addition, molecular dynamic simulation (MD) was also performed for 140 ns to explore the stability behavior of the main targets and inhibitor complexes as well as the binding mechanics of the ligand to the target proteins. The obtained MD results followed by absolute binding energy calculation confirm that the binding of emetine at the level of the various receptors is more stable. The complex EmetineNSP15, mechanistically was stabilized as follows: Emetine first binds to the monomer, after, binds to the second inducing the formation of a dimer which in turn leading to the formation of complex that simulation stabilizes it at a value less than 5 Å. Overall, supported by the powerful and good pharmacokinetic data of Emetine, our findings with clinical trials may be helpful to confirm that Emetine could be promoted in the prevention and eradication of COVID-19 by reducing the severity in the infected persons and therefore can open possible new strategies for drug repositioning. Communicated by Ramaswamy H. Sarma.

DNA intercalators alkaloids as Potential candidates to fight COVID-19 disease: Systematic review

The main objective of the current systematic review was to report the antiviral and anti-inflammatory effects of bioactive molecules class known as alkaloids against SARS-COV-2 disease. These bioactive compounds were characterized by their potential replication inhibitory ability by DNA intercalating effect, and might be powerful agents against infections caused by several viruses, therefore it can be a viable strategy for COVID-19 management. PubMed, ScienceDirect, Google Scholar and SpringerLink, databases have been chosen to look for keywords like DNA intercalators, alkaloids, antiviral activity, anti-inflammatory effect, coronavirus, SARS-CoV-2. Two reviewers have evaluated the quality of 60 articles extracted from the four databases till 15th of May 2021, using inclusions and exclusions criteria, 25 papers were accepted and treated in this systematic review, performed based on PRISMA protocol. Results disclosed that alkaloids have key roles in viral replication inhibition, quinine and emetine showed a noticeable therapeutic effect against SARS-COV-2 virus, however emetine revealed modifications in the electrocardiogram (ECG), unlike sanguinarine and berberine that showed low human toxicity. Tetrandrine, fangchinoline and cepharantine could be classified as remedies in case of Coronavirus ailment. Chelidonine, coptisine, skimmianine, protropine, palmatine, cinchonine, harmine and dictamine represented important agents for clinical researches or as precursors for antiviral drug’s formulation.

Phytochemical Contents, Biological Activities and Therapeutic Applications of Hedera Helix (Ivy Leaf) Extracts: A Review

Background: Herbs have long been used as natural therapeutics, and recent controlled clinical studies have confirmed some of the presumed benefits. Hedera helix(ivy leaves) is a valuable common form related to the family Araliaceae. Many herbal preparations include extracts from their leaves as the principle active ingredient. Objective: The objective of this article is to summarize the pharmacological activities and phyto-chemical screening of H. helix. Methods: To prepare this article, the data was collected from different sources, including books, th-esis, research and etc. Results: The all-published studies depend on isolation, identification, and characterization of different active constituents of H. helix leaves, followed by the determination of biological activities in vivo and in vivo. Chemical screening has shown that H. helix leaves are a rich source of phytochem-icals demonstrating therapeutic activities, such as sterols, tannins, terpenoids, glycosides, phenols, emetine alkaloids, flavonoids, saponins, volatile and fixed oils, vitamins, carbohydrates, reducing sugars, and minerals. Further, studies of disease models and clinical trials have demonstrated an-ti-inflammatory, analgesic, cough suppressant, expectorant, anticancer, antimicrobial, anticoagu-lant, and smooth muscle relaxant activities. Conclusion: This review summarizes the bioactive constituents of H. helix leaves and their under-lying pharmacological mechanisms, clinical efficacies, and safety profiles. We also suggest potential therapeutic uses for COVID-19.

Application of emetine in SARS-CoV-2 treatment: regulation of p38 MAPK signaling pathway for preventing emetine-induced cardiac complications.

Emetine is one of the most highly potent anti-SARS-CoV-2 agents ever identified. In addition to having strong anti-SARS-CoV-2 activities, emetine has other valuable therapeutic effects such as strong anti-inflammatory and anti-arterial pulmonary hypertension (APH) properties, which are suitable for the treatment of COVID-19. Its proper concomitant therapeutic effect has led researchers to test this compound in clinical trials to combat COVID-19. However, due to the risks of cardiac complications, very low doses of emetine have been used in different studies, which may not have significant therapeutic effects. The p38 MAPK signaling pathway is strongly highlighted as an important operator in cardiac cellular damages such as disruption of cardiac fibroblast function and myopathy/cardiomyopathy. Inhibition of this pathway by appropriate inhibitors has also been considered by scientists as a promising strategy for the treatment of fatal host-related hyper-inflammatory immune responses following SARS-CoV-2 infection. Although remarkable stimulatory effects of emetine on activation of the p38 MAPK pathway have been reported in recent studies and strong evidence suggests that this pathway plays an effective role in the emetine's toxicities, it has not been discussed yet that emetine induced cellular cardiac complications may be due to the activation of this critical pathway. Considering these points could lead to the finding of strategies for applying the valuable potential of emetine in the treatment of COVID-19 at low risks.

Exploring the potential mechanism of emetine against coronavirus disease 2019 combined with lung adenocarcinoma: bioinformatics and molecular simulation analyses.

BACKGROUND: Patients with lung adenocarcinoma (LUAD) may be more predisposed to coronavirus disease 2019 (COVID-19) and have a poorer prognosis. Currently, there is still a lack of effective anti-LUAD/COVID-19 drugs. Thus, this study aimed to screen for an effective anti-LUAD/COVID-19 drug and explore the potential mechanisms. METHODS: Firstly, we performed differentially expressed gene (DEG) analysis on LUAD transcriptome profiling data in The Cancer Genome Atlas (TCGA), where intersections with COVID-19-related genes were screened out. Then, we conducted Cox proportional hazards analyses on these LUAD/COVID-19 DEGs to construct a risk score. Next, LUAD/COVID-19 DEGs were uploaded on Connectivity Map to obtain drugs for anti-LUAD/COVID-19. Finally, we used network pharmacology, molecular docking, and molecular dynamics (MD) simulation to explore the drug's therapeutic targets and potential mechanisms for anti-LUAD/COVID-19. RESULTS: We identified 230 LUAD/COVID-19 DEGs and constructed a risk score containing 7 genes (BTK, CCL20, FURIN, LDHA, TRPA1, ZIC5, and SDK1) that could classify LUAD patients into two risk groups. Then, we screened emetine as an effective drug for anti-LUAD/COVID-19. Network pharmacology analyses identified 6 potential targets (IL6, DPP4, MIF, PRF1, SERPING1, and SLC6A4) for emetine in anti-LUAD/COVID-19. Molecular docking and MD simulation analyses showed that emetine exhibited excellent binding capacities to DDP4 and the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). CONCLUSIONS: This study found that emetine may inhibit the entry and replication of SARS-CoV-2 and enhance tumor immunity by bounding to DDP4 and Mpro.

Therapeutic potential of plant secondary metabolites in treatment of respiratory viral diseases: A review

Respiratory viral infections are a major public health concern because of their global occurrence, ease of spread and considerable morbidity and mortality. Medical treatments for viral respiratory diseases primarily involve providing relief from symptoms like pain and discomfort rather than treating the infection. Very few antiviral medications have been approved with restrictive usage, high cost, unwanted side effects and limited availability. Plants with their unique metabolite composition and high remedial values offer unique preventive and therapeutic efficacy in treatment of viral infections. The present review is focused on the types and mode of action of plant secondary metabolites that have been used successfully ί in the treatment of infections caused by respiratory viruses like Influenza, SARS, MERS, RSV etc. Plant metabolites such as phenolics, alkaloids, terpenoids and oligosaccharides inhibit attachment and entry of the virus. Others such as flavonoids, viz quercetin and baicalein, alkaloids viz sanguinarine, berberine and emetine, specific lipids and fatty acids prevent viral replication and protein synthesis. These metabolites have the potential to be used as lead molecules that can be optimized to develop potent drugs for effectively combating pandemics caused by respiratory viruses.

Emetine, Ipecac, Ipecac Alkaloids and Analogues as Potential Antiviral Agents for Coronaviruses.

The COVID-19 coronavirus is currently spreading around the globe with limited treatment options available. This article presents the rationale for potentially using old drugs (emetine, other ipecac alkaloids or analogues) that have been used to treat amoebiasis in the treatment of COVID-19. Emetine had amongst the lowest reported half-maximal effective concentration (EC50) from over 290 agents screened for the Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) coronaviruses. While EC50 concentrations of emetine are achievable in the blood, studies show that concentrations of emetine can be almost 300 times higher in the lungs. Furthermore, based on the relative EC50s of emetine towards the coronaviruses compared with Entamoeba histolytica, emetine could be much more effective as an anti-coronavirus agent than it is against amoebiasis. This paper also discusses the known side effects of emetine and related compounds, how those side effects can be managed, and the optimal method of administration for the potential treatment of COVID-19. Given the serious and immediate threat that the COVID-19 coronavirus poses, our long history with emetine and the likely ability of emetine to reach therapeutic concentrations within the lungs, ipecac, emetine, and other analogues should be considered as potential treatment options, especially if in vitro studies confirm viral sensitivity.

Targeting mucormycosis polyprotein (RVT_1 region) through antifungal phytochemicals: An in-silico perspective

Mucormycosis has become a global issue due to its potential to infect and destroy organs, as well as its high fatality rate. Co-infecting with Covid 19 or when infecting after Covid 19, it becomes more lethal. Several antifungal medicines have been utilized to treat this illness, but they come with a slew of dangerous side effects. Hence, using various computational tools;the current study was attempted to determine several antifungal plant metabolites that can act as inhibitory agents of Rhizopus oryzae, which is responsible for 70% of mucormycosis cases. In total, 56 antifungal plant metabolites were evaluated against Rhizopus oryzae polyprotein (RVT_1 region). Four metabolites, i.e., emetine, jatrorrhizine, isoboldine, and 6-a-hydroxymedicarpin showed maximum binding affinity with the targeted polyprotein (RVT_1 region) according to the lowest global binding energy and binding energy. The fungal protein's critical binding sites and drug surface hotspots were uncovered. The best candidates were gone through an ADME (absorption, distribution, metabolism, and excretion) analysis to observe their drug profiles. According to the findings, none have any side effects that could interfere with their drug likeness efficiency as well as no significant toxic effects and allergenicity were found. The majority of the target classes for proposed drug candidates were enzyme groups (e.g., oxidoreductase, family a g protein-coupled receptor, enzyme, protease). Furthermore, emetine and jatrorrhizine have been proposed to have inhibitory potency against covid 19 in several studies. Hence, we strongly propose additional in vivo trials in order to experimentally validate our findings, based on the optimistic results.

Low dose of emetine as potential anti-SARS-CoV-2 virus therapy: preclinical in vitro inhibition and in vivo pharmacokinetic evidences.

The global pandemic of COVID-19 has attracted extensive drug searching interets for the new coronavirus SARS-CoV-2. Although currently several of clinically used "old" drugs have been repurposed to this new disease for the urgent clinical investigation, there is still great demand for more effective therapies for the anti-infections. Here we report the discovery that an "old" drug Emetine could potently inhibit SARS-CoV-2 virus replication and displayed virus entry blocking effect in Vero cells at low dose. In addition, Emetine could significantly reduce the lipopolysaccharide (LPS) induced interleukin-6 (IL-6) protein level and moderately reduce the tumor necrosis factor (TNF-α) protein level in the M1 polarized THP-1 macrophages. In vivo animal pharmacokinetics (PK) study revealed that Emetine was enriched in the lung tissue and had a long retention time (over 12 h). With 1 mg/kg single oral dose, the effective concentration of Emetine in lung was up to 1.8 µM (mice) and 1.6 µM (rats) at 12 h, which is over 200-fold higher than the EC50 of the drug. The potent in vitro antiviral replication efficacy and the high enrichment in target tissue, combining with the well documented safety profiles in human indicate that low dose of Emetine might be a potentially effective anti-SARS-CoV-2 infection therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s43556-020-00018-9.

Clinical efficacy of low-dose emetine for patients with COVID-19: a real-world study.

OBJECTIVE: Emetine, an isoquinoline alkaloid that is enriched at high concentrations in the lung, has shown potent in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The aim of this study was to better understand the effectiveness of low-dose emetine for patients with coronavirus disease 2019 (COVID-19). METHODS: In this real-world study, 63 patients with mild or common COVID-19 were recruited from Wuhan Fangcang Shelter Hospital and five COVID-19-designated hospitals in Anhui Province, China from February to March 2020. Thirty-nine patients from Wuhan Fangcang Shelter Hospital were assigned to a pragmatic randomized controlled clinical trial, and 24 patients from the 5 COVID-19-designated hospitals in Anhui Province underwent a real-world study. The medication course of emetine was less than 10 days. The main symptoms and adverse reactions of all patients were observed and recorded. The primary outcome measure was the time required for a negative SARS-CoV-2 RNA result or the negative result rate on day 10. Secondary outcomes included axillary temperature, transcutaneous oxygen saturation, and respiratory frequency recovery. The study was approved by the Ethics Committee of The First Affiliated Hospital of Anhui Medical University on February 20, 2019 (approval No. PJ2020-03-19) and was registered with the Chinese Clinical Trial Registry on February 20, 2019 (registration number: ChiCTR2000030022). RESULTS: The oxygen saturation values were higher in the treatment group than in the control group on the first day after enrollment for patients treated at Fangcang Shelter Hospital. The axillary body temperature, respiratory rate, and oxygen saturation among patients in Fangcang Shelter Hospital were related to the time effect but not to the intervention measures. The respiratory rate and oxygen saturation of patients in the Anhui designated hospitals were related to the intervention measures but not to the time effect. The axillary body temperature of patients in Anhui designated hospitals was related to the time effect but not to the intervention measures. CONCLUSION: Our preliminary study shows that low-dose emetine combined with basic conventional antiviral drugs improves clinical symptoms in patients with mild and common COVID-19 without apparent adverse effects, suggesting that moderately increased doses of emetine may have good potential for treatment and prevention of COVID-19.

Zinc supplementation augments the suppressive effects of repurposed NF-κB inhibitors on ACE2 expression in human lung cell lines.

AIMS: Angiotensin-converting enzyme 2 (ACE2) is a key negative regulator of the renin-angiotensin system and also a major receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we reveal a role for NF-κB in human lung cell expression of ACE2, and we further explore the potential utility of repurposing NF-κB inhibitors to downregulate ACE2. MAIN METHODS: Expression of ACE2 was assessed by Western blotting and RT-qPCR in multiple human lung cell lines with or without NF-κB inhibitor treatment. Surface ACE2 expression and intracellular reactive oxygen species (ROS) levels were measured with flow cytometry. p50 was knocked down with siRNA. Cytotoxicity was monitored by PARP cleavage and MTS assay. KEY FINDINGS: Pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor, suppressed endogenous ACE2 mRNA and protein expression in H322M and Calu-3 cells. The ROS level in H322M cells was increased after PDTC treatment, and pretreatment with N-acetyl-cysteine (NAC) reversed PDTC-induced ACE2 suppression. Meanwhile, treatment with hydrogen peroxide augmented ACE2 suppression in H322M cells with p50 knockdown. Two repurposed NF-κB inhibitors, the anthelmintic drug triclabendazole and the antiprotozoal drug emetine, also reduced ACE2 mRNA and protein levels. Moreover, zinc supplementation augmented the suppressive effects of triclabendazole and emetine on ACE2 expression in H322M and Calu-3 cells. SIGNIFICANCE: These results suggest that ACE2 expression is modulated by ROS and NF-κB signaling in human lung cells, and the combination of zinc with triclabendazole or emetine shows promise for clinical treatment of ACE2-related disease.

Ribopuromycylation in Coronavirus-Infected Cells.

Ribopuromycylation enables the visualization and quantitation of translation on a cellular level by immunofluorescence or in total using standard western blotting. This technique uses ribosome catalyzed puromycylation of nascent chains followed by immobilization on the ribosome by antibiotic chain elongation inhibitor emetine. Detection of puromycylated ribosome-bound nascent chains can then be achieved using a puromycin-specific antibody.

Deep Transfer Learning Approach for Automatic Recognition of Drug Toxicity and Inhibition of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes COVID-19 and is responsible for the ongoing pandemic. Screening of potential antiviral drugs against SARS-CoV-2 depend on in vitro experiments, which are based on the quantification of the virus titer. Here, we used virus-induced cytopathic effects (CPE) in brightfield microscopy of SARS-CoV-2-infected monolayers to quantify the virus titer. Images were classified using deep transfer learning (DTL) that fine-tune the last layers of a pre-trained Resnet18 (ImageNet). To exclude toxic concentrations of potential drugs, the network was expanded to include a toxic score (TOX) that detected cell death (CPETOXnet). With this analytic tool, the inhibitory effects of chloroquine, hydroxychloroquine, remdesivir, and emetine were validated. Taken together we developed a simple method and provided open access implementation to quantify SARS-CoV-2 titers and drug toxicity in experimental settings, which may be adaptable to assays with other viruses. The quantification of virus titers from brightfield images could accelerate the experimental approach for antiviral testing.

Emetine suppresses SARS-CoV-2 replication by inhibiting interaction of viral mRNA with eIF4E.

Emetine is a FDA-approved drug for the treatment of amebiasis. Previously we demonstrated the antiviral efficacy of emetine against some RNA and DNA viruses. In this study, we evaluated the in vitro antiviral efficacy of emetine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and found it to be a low nanomolar (nM) inhibitor. Interestingly, emetine exhibited protective efficacy against lethal challenge with infectious bronchitis virus (IBV; a chicken coronavirus) in the embryonated chicken egg infection model. Emetine treatment led to a decrease in viral RNA and protein synthesis without affecting other steps of viral life cycle such as attachment, entry and budding. In a chromatin immunoprecipitation (CHIP) assay, emetine was shown to disrupt the binding of SARS-CoV-2 mRNA with eIF4E (eukaryotic translation initiation factor 4E, a cellular cap-binding protein required for initiation of protein translation). Further, molecular docking and molecular dynamics simulation studies suggested that emetine may bind to the cap-binding pocket of eIF4E, in a similar conformation as m7-GTP binds. Additionally, SARS-CoV-2 was shown to exploit ERK/MNK1/eIF4E signalling pathway for its effective replication in the target cells. Collectively our results suggest that further detailed evaluation of emetine as a potential treatment for COVID-19 may be warranted.

Emetine Is Not Ipecac: Considerations for Its Use as Treatment for SARS-CoV2.

Emetine is a potent antiviral that acts on many viruses in the low-nM range, with several studies in animals and humans demonstrating antiviral activity. Historically, emetine was used to treat patients with Spanish influenza, in the last stages of the pandemic in the early 1900s. Some of these patients were "black" with cyanosis. Emetine rapidly reversed the cyanosis and other symptoms of this disease in 12-24 h. However, emetine also has been shown to have anti-inflammatory properties and it appears it is these anti-inflammatory properties that were responsible for the effects seen in patients with Spanish influenza. Emetine, in the past, has also been used in 10s to 100s of millions of people at a dose of ~60 mg daily to treat amoebiasis. Based on viral inhibition data we can calculate a likely SARS-CoV2 antiviral dose of ~1/10th the amoebiasis dose, which should dramatically reduce the risk of any side effects. While there are no anti-inflammatory dose response data available, based on the potential mode of action, the anti-inflammatory actions may also occur at low doses. This paper also examines the toxicity of emetine seen in clinical practice and that seen in the laboratory, and discusses the methods of administration aimed at reducing side effects if higher doses were found to be necessary. While emetine is a "pure drug" as it is extracted from ipecac, some of the differences between emetine and ipecac are also discussed.

Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro.

An escalating pandemic by the novel SARS-CoV-2 virus is impacting global health and effective therapeutic options are urgently needed. We evaluated the in vitro antiviral effect of compounds that were previously reported to inhibit coronavirus replication and compounds that are currently under evaluation in clinical trials for SARS-CoV-2 patients. We report the antiviral effect of remdesivir, lopinavir, homorringtonine, and emetine against SARS-CoV-2 virus in Vero E6 cells with the estimated 50% effective concentration at 23.15 µM, 26.63 µM, 2.55 µM and 0.46 µM, respectively. Ribavirin or favipiravir that are currently evaluated under clinical trials showed no inhibition at 100 µM. Synergy between remdesivir and emetine was observed, and remdesivir at 6.25 µM in combination with emetine at 0.195 µM may achieve 64.9% inhibition in viral yield. Combinational therapy may help to reduce the effective concentration of compounds below the therapeutic plasma concentrations and provide better clinical benefits.