Antiviral activity of medicinal plant-derived products against SARS-CoV-2

This review presents information from several studies that have demonstrated the antiviral activity of extracts (Andrographis paniculata, Artemisia annua, Artemisia afra, Cannabis sativa, Curcuma longa, Echinacea purpurea, Olea europaea, Piper nigrum, and Punica granatum) and phytocompounds derived from medicinal plants (artemisinins, glycyrrhizin, and phenolic compounds) against SARS-CoV-2. A brief background of the plant products studied, the methodology used to evaluate the antiviral activity, the main findings from the research, and the possible mechanisms of action are presented. These plant products have been shown to impede the adsorption of SARS-CoV-2 to the host cell, and prevent multiplication of the virus post its entry into the host cell. In addition to antiviral activity, the plant products have also been demonstrated to exert an immunomodulatory effect by controlling the excessive release of cytokines, which is commonly associated with SARS-CoV-2 infections.     

Antiviral Activity of Nitrosonium Cations against SARS-CoV-2 on a Syrian Hamster Model

Biophysics - The antiviral action of binuclear dinitrosyl iron complexes with glutathione along with diethyldithiocarbamate against the SARS-CoV-2 virus has been demonstrated on a Syrian hamster...     

Antiviral activities of mycophenolic acid and IMD-0354 against SARS-CoV-2

In this study, the anti–severe acute respiratory syndrome coronavirus-2 (anti-SARS-CoV-2) activity of mycophenolic acid (MPA) and IMD-0354 was analyzed. These compounds were chosen based on their antiviral activities against other coronaviruses. Because they also inhibit dengue virus (DENV) infection, other anti-DENV compounds/drugs were also assessed. On SARS-CoV-2-infected VeroE6/TMPRSS2 monolayers, both MPA and IMD-0354, but not other anti-DENV compounds/drugs, showed significant anti-SARS-CoV-2 activity. Although MPA reduced the viral RNA level by only approximately 100-fold, its half maximal effective concentration was as low as 0.87 µ m , which is easily achievable at therapeutic doses of mycophenolate mofetil. MPA targets the coronaviral papain-like protease and an in-depth study on its mechanism of action would be useful in the development of novel anti-SARS-CoV-2 drugs.     

Comparative Antiviral Efficacy of Viral Protease Inhibitors against the Novel SARS-CoV-2 In Vitro

Virologica Sinica - The recent outbreak of novel coronavirus pneumonia (COVID-19) caused by a new coronavirus has posed a great threat to public health. Identifying safe and effective antivirals is...     

Mechanisms of Antiviral Immune Evasion of SARS-CoV-2

Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is characterized by a delayed interferon (IFN) response and high levels of proinflammatory cytokine expression. Type I and III IFNs serve as a first line of defense during acute viral infections and are readily antagonized by viruses to establish productive infection. A rapidly growing body of work has interrogated the mechanisms by which SARS-CoV-2 antagonizes both IFN induction and IFN signaling to establish productive infection. Here, we summarize these findings and discuss the molecular interactions that prevent viral RNA recognition, inhibit the induction of IFN gene expression, and block the response to IFN treatment. We also describe the mechanisms by which SARS-CoV-2 viral proteins promote host shutoff. A detailed understanding of the host-pathogen interactions that unbalance the IFN response is critical for the design and deployment of host-targeted therapeutics to manage COVID-19.     

Antiviral activity of novel 2'-fluoro-6'-methylene-carbocyclic adenosine against wild-type and drug-resistant hepatitis B virus mutants

Novel 2'-fluoro-6'-methylene-carbocyclic adenosine (9) was synthesized and evaluated its anti-HBV activity. The titled compound demonstrated significant antiviral activity against wild-type as well as lamivudine, adefovir and double lamivudine/entecavir resistant mutants. Molecular modeling study indicate that the 2'-fluoro moiety by a hydrogen bond, as well as the van der Waals interaction of the carbocyclic ring with the phenylalanine moiety of the polymerase promote the positive binding, even in the drug resistant mutants.     

Antiviral activity of a bile pigment, biliverdin, against human herpesvirus 6 (HHV-6) in vitro.

Biliverdin (BV), a bile pigment, was examined for its antiviral activity against human herpesvirus-6 (HHV-6) in vitro. BV (10 micrograms/ml) markedly inhibited HHV-6 replication in MT-4 cells when the cells were treated during a virus adsorption period. Its antiviral effect was weakened when cells were treated after adsorption. Treatment of cells with BV (40 micrograms/ml) 3 hr after virus infection had no inhibitory effect on virus replication. Virus replication was also significantly inhibited by treatment of MT-4 cells with BV (10 micrograms/ml) before infection, while the virions were not inactivated by BV (20 micrograms/ml). Bilirubin and urobilin, metabolic derivatives of BV, showed slight inhibitory effects on virus replication in the cells. On the other hand, BV had no potent inhibitory activity in the replication of herpes simplex virus-1 or human cytomegalovirus. These observations suggest that BV could interact with MT-4 cells to inhibit an early stage of HHV-6 infection in a virus-specific manner.     

SARS-CoV-2 antibodies protect against reinfection for at least 6 months in a multicentre seroepidemiological workplace cohort

Identifying the potential for SARS-CoV-2 reinfection is crucial for understanding possible long-term epidemic dynamics. We analysed longitudinal PCR and serological testing data from a prospective cohort of 4,411 United States employees in 4 states between April 2020 and February 2021. We conducted a multivariable logistic regression investigating the association between baseline serological status and subsequent PCR test result in order to calculate an odds ratio for reinfection. We estimated an odds ratio for reinfection ranging from 0.14 (95% CI: 0.019 to 0.63) to 0.28 (95% CI: 0.05 to 1.1), implying that the presence of SARS-CoV-2 antibodies at baseline is associated with around 72% to 86% reduced odds of a subsequent PCR positive test based on our point estimates. This suggests that primary infection with SARS-CoV-2 provides protection against reinfection in the majority of individuals, at least over a 6-month time period. We also highlight 2 major sources of bias and uncertainty to be considered when estimating the relative risk of reinfection, confounders and the choice of baseline time point, and show how to account for both in reinfection analysis.

Identifying the potential for SARS-CoV-2 reinfection is crucial for understanding possible long-term epidemic dynamics. Analysis of a seroepidemiological cohort suggests that primary infection with SARS-CoV-2 protects against reinfection in the majority of individuals, at least over a six month period.     

Characterization of raloxifene as a potential pharmacological agent against SARS-CoV-2 and its variants

The new coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic, which so far has caused over 6 million deaths in 2 years, despite new vaccines and antiviral medications. Drug repurposing, an approach for the potential application of existing pharmaceutical products to new therapeutic indications, could be an effective strategy to obtain quick answers to medical emergencies. Following a virtual screening campaign on the most relevant viral proteins, we identified the drug raloxifene, a known Selective Estrogen Receptor Modulator (SERM), as a new potential agent to treat mild-to-moderate COVID-19 patients. In this paper we report a comprehensive pharmacological characterization of raloxifene in relevant in vitro models of COVID-19, specifically in Vero E6 and Calu-3 cell lines infected with SARS-CoV-2. A large panel of the most common SARS-CoV-2 variants isolated in Europe, United Kingdom, Brazil, South Africa and India was tested to demonstrate the drug’s ability in contrasting the viral cytopathic effect (CPE). Literature data support a beneficial effect by raloxifene against the viral infection due to its ability to interact with viral proteins and activate protective estrogen receptor-mediated mechanisms in the host cells. Mechanistic studies here reported confirm the significant affinity of raloxifene for the Spike protein, as predicted by in silico studies, and show that the drug treatment does not directly affect Spike/ACE2 interaction or viral internalization in infected cell lines. Interestingly, raloxifene can counteract Spike-mediated ADAM17 activation in human pulmonary cells, thus providing new insights on its mechanism of action. A clinical study in mild to moderate COVID-19 patients ({"type":"clinical-trial","attrs":{"text":"NCT05172050","term_id":"NCT05172050"}}NCT05172050) has been recently completed. Our contribution to evaluate raloxifene results on SARS-CoV-2 variants, and the interpretation of the mechanisms of action will be key elements to better understand the trial results, and to design new clinical studies aiming to evaluate the potential development of raloxifene in this indication.Subject terms: Viral infection, Preclinical research     

Metal-based complexes against SARS-CoV-2

BioMetals - The first appearance of SARS-CoV-2 is dated back to 2019. This new member of the coronavirus family has caused more than 5 million deaths worldwide up until the end of January 2022. At...     

Timing vaccination against SARS-CoV-2

Circadian rhythms play an important role in balancing innate and adaptive immune responses.In a recent study in Cell Research,Zhang et al.studied the immunologi...     

Glycyrrhizic acid exerts inhibitory activity against the spike protein of SARS-CoV-2

Coronavirus causes a disease with high infectivity and pathogenicity, especially SARS in 2003, MERS in 2012, and COVID-2019 currently. The spike proteins of these coronaviruses are critical for host cell entry by receptors. Thus, searching for broad-spectrum anti-coronavirus candidates, such as spike protein inhibitors, is vital and desirable due to the mutations in the spike protein. In this study, a combination of computer-aided drug design and biological verification was used to discover active monomers from traditional Chinese medicine. Surface plasmon resonance (SPR) assays and NanoBit assays were used to verify the predicated compounds with their binding activities to spike proteins and inhibitory activities on the SARS-CoV-2 RBD/ACE2 interaction, respectively. Furthermore, an MTT assay was used to evaluate the cell toxicities of active compounds. As a result, glycyrrhizic acid (ZZY-44) was found to be the most efficient and nontoxic broad-spectrum anti-coronavirus molecule in vitro, especially, the significant effect on SARS-CoV-2, which provided a theoretical basis for the study of the pharmacodynamic material basis of traditional Chinese medicine against SARS-CoV-2 and offered a lead compound for further structural modification in order to obtain more effective candidate drugs against SARS-CoV-2.     

Antiviral activity of recombinant cyanovirin-N against HSV-1

In this study, a standard strain of HSV-1 (strain SM₄₄) was used to investigate the antiviral activity of the recombinant Cyanovirin-N (CV-N) against Herpes simplex virus type 1 (HSV-1) in vitro and in vivo. Cytopathic effect (CPE) and MTT assays were used to evaluate the effect of CV-N on HSV-1 in Vero cells. The number of copies of HSV-DNA was detected by real-time fluorescence quantitative PCR (FQ-PCR). The results showed that CV-N had a low cytotoxicity on Vero cells with a CC₅₀ of 359.03±0.56 μg/mL, and that it could not directly inactivate HSV-1 infectivity. CV-N not only reduced the CPE of HSV-1 when added before or after viral infection, with a 50% inhibitory concentration (IC₅₀) with 2.26 and 30.16μg/mL respectively, but it also decreased the copies of HSV-1 DNA in infected host cells. The encephalitis model for HSV-1 infection was conducted in Kunming mice, and treated with three dosages of CV-N (0.5, 5 &; 10 mg/kg) which was administered intraperitoneally at 2h, 3d, 5d, 7d post infection. The duration for the appearance of symptoms of encephalitis and the survival days were recorded and brain tissue samples were obtained for pathological examination (HE staining). Compared with the untreated control group, in the 5mg/kg CV-N and 10mg/kg CV-N treated groups, the mice suffered light symptoms and the number of survival days were more than 9d and 14d respectively. HE staining also showed that in 5mg/kg CV-N and 10mg/kg CV-N treated groups, the brain cells did not show visible changes, except for a slight inflammation. Our results demonstrated that CV-N has pronounced antiviral activity against HSV-1 both in vitro and in vivo, and it would be a promising new candidate for anti-HSV therapeutics.     

Antiviral activity of (+)-sattabacin against varicella zoster

The first report of the antiviral activity of (+)-sattabacin against varicella-zoster virus (VZV) is described. Our results show that (+)-sattabacin potently inhibits the growth of VZV at concentrations in the range of other drugs commonly prescribed for VZV infection. Experiments detailing the synthesis of (+)-sattabacin, quantification of cytotoxicity and gene expression data in human fibroblast cells are also presented. Gene expression data was obtained through microarray analysis from human fibroblast cells exposed to sattabacin in order to identify a possible mechanism by which (+)-sattabacin inhibits VZV replication.     

Antiviral activity of an N-allyl acridone against dengue virus

Background

Dengue virus (DENV), a member of the family Flaviviridae, is at present the most widespread causative agent of a human viral disease transmitted by mosquitoes. Despite the increasing incidence of this pathogen, there are no antiviral drugs or vaccines currently available for treatment or prevention. In a previous screening assay, we identified a group of N-allyl acridones as effective virus inhibitors. Here, the antiviral activity and mode of action targeted to viral RNA replication of one of the most active DENV-2 inhibitors was further characterized.

Results

The compound 10-allyl-7-chloro-9(10H)-acridone, designated 3b, was active to inhibit the in vitro infection of Vero cells with the four DENV serotypes, with effective concentration 50% (EC₅₀) values in the range 12.5-27.1 μM, as determined by virus yield inhibition assays. The compound was also effective in human HeLa cells. No cytotoxicity was detected at 3b concentrations up to 1000 μM. Mechanistic studies demonstrated that virus entry into the host cell was not affected, whereas viral RNA synthesis was strongly inhibited, as quantified by real time RT-PCR. The addition of exogenous guanosine together with 3b rescued only partially the infectivity of DENV-2.

Conclusions

The acridone derivative 3b selectively inhibits the infection of Vero cells with the four DENV serotypes without a direct interaction with the host cell or the virion but interfering specifically with the intracellular virus multiplication. The mode of antiviral action for this acridone apparently involves the cellular enzyme inosine-monophospahe dehydrogenase together with another still unidentified target related to DENV RNA synthesis.     

Antiviral activity of pyridyl imidazolidinones against enterovirus 71 variants

Pyridyl imidazolidinone is a novel class of capsid binder which can inhibit enterovirus 71 (EV71). In this study, we tested the susceptibility of six recombinant viruses with different single-site mutations in VP1. Eleven modified pyridyl imidazolidinones were synthesized and used to probe the interaction between these compounds and the EV71 VP1 protein. We found that the D31N or E98K mutant viruses were susceptible to bulkier compounds, which suggested that mutations at these two sites in VP1 may widen the hydrophobic pocket of VP1, allowing bulkier compounds to enter and interfere VP1-receptor binding. Additionally, the Y116H mutant was more resistant to pyridyl imidazolidinone compounds containing a methyl group in the central position of the hydrophobic linker. When a trifluoromethyl group was substituted for the methyl group in the middle of the linker chain, the inhibitory effect was totally abolished in the Y116H mutant, suggesting that the interaction between Tyr (Y) 116 of VP1 and the central position of the linker chain of pyridyl imidazolodinone is very important for drug efficacy. A V192M mutant was resistant to most of the derivatives, indicating that residue 192 is a key mutation for resistance to pyridyl imidazolidinone.