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Viruses Feb 2023Echinocandin antifungal drugs, including micafungin, anidulafungin, and caspofungin, have been recently reported to exhibit antiviral effects against various viruses...
Echinocandin antifungal drugs, including micafungin, anidulafungin, and caspofungin, have been recently reported to exhibit antiviral effects against various viruses such as flavivirus, alphavirus, and coronavirus. In this study, we focused on micafungin and its derivatives and analyzed their antiviral activities against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The micafungin derivatives Mi-2 and Mi-5 showed higher antiviral activity than micafungin, with 50% maximal inhibitory concentration (IC) of 5.25 and 6.51 µM, respectively (3.8 to 4.7-fold stronger than micafungin) and 50% cytotoxic concentration (CC) of >64 µM in VeroE6/TMPRSS2 cells. This high anti-SARS-CoV-2 activity was also conserved in human lung epithelial cell-derived Calu-3 cells. Micafungin, Mi-2, and Mi-5 were suggested to inhibit the intracellular virus replication process; additionally, these compounds were active against SARS-CoV-2 variants, including Delta (AY.122, hCoV-19/Japan/TY11-927/2021), Omicron (BA.1.18, hCoV-19/Japan/TY38-873/2021), a variant resistant to remdesivir (R10/E796G C799F), and a variant resistant to casirivimab/imdevimab antibody cocktail (E406W); thus, our results provide basic evidence for the potential use of micafungin derivatives for developing antiviral agents.
Topics: Humans; Antiviral Agents; COVID-19; Micafungin; RNA Replication; RNA, Viral; SARS-CoV-2
PubMed: 36851666
DOI: 10.3390/v15020452 -
Antiviral Research Sep 2022Foot-and-mouth disease (FMD) is an acute contagious disease of cloven-hoofed animals such as cows, pigs, sheep, and deer. The current emergency FMD vaccines, to induce...
Foot-and-mouth disease (FMD) is an acute contagious disease of cloven-hoofed animals such as cows, pigs, sheep, and deer. The current emergency FMD vaccines, to induce early protection, have limited use, as their protective effect in pigs does not begin until 7 days after vaccination. Therefore, the use of antiviral agents would be required for reducing the spread of foot-and-mouth disease virus (FMDV) during outbreaks. Vesatolimod (GS-9620), a toll-like receptor 7 agonist, is an antiviral agent against various human disease-causing viruses. However, its antiviral effect against FMDV has not been reported yet. The aim of this study was to investigate the antiviral effects of GS-9620 against FMDV both in vitro and in vivo. The inhibitory effect of GS-9620 on FMDV in swine cells involved the induction of porcine interferon (IFN)-α and upregulation of interferon-simulated genes. Protective effect in mice injected with GS-9620 against FMDV was maintained for 5 days after injection, and cytokines such as IFN-γ, interleukin (IL)-12, IL-6, and IFN-γ inducible protein-10 could be detected following the treatment with GS-9620. Furthermore, the combination of GS-9620 with an FMD-inactivated vaccine was found to be highly effective for early protection in mice. Overall, we suggest GS-9620 as a novel and effective antiviral agent for controlling FMDV infection.
Topics: Animals; Antiviral Agents; Cattle; Deer; Foot-and-Mouth Disease; Foot-and-Mouth Disease Virus; Humans; Interferon-alpha; Mice; Pteridines; Sheep; Swine; Viral Vaccines
PubMed: 35863499
DOI: 10.1016/j.antiviral.2022.105384 -
Journal of Agricultural and Food... Mar 2022In response to the invasion of plant viruses and pathogenic fungi, higher plants produce defensive allelochemicals. Finding candidate varieties of botanical pesticides...
In response to the invasion of plant viruses and pathogenic fungi, higher plants produce defensive allelochemicals. Finding candidate varieties of botanical pesticides based on allelochemicals is one of the important ways to create efficient and green pesticides. Here, a series of camalexin derivatives based on a phytoalexin camalexin scaffold were designed, synthesized, and assessed for their antiviral and fungicidal activities systematically. Most of these camalexin derivatives exhibited better antiviral activities against tobacco mosaic virus (TMV) than the control antiviral agent ribavirin. Under the same test conditions, the anti-TMV activities of compounds , , , and - were found to be equivalent to or better than that of ningnanmycin, an agricultural cytosine nucleoside antibiotic with excellent protective effect. The antiviral mechanism research showed that compound could cause 20S CP disk fusion and disintegration, thus affecting the assembly of virus particles. The results of molecular docking indicate that there were obvious hydrogen bonds between compounds , , and and TMV CP. The binding constants of compounds and to TMV CP were also calculated using fluorescence titration. These camalexin derivatives also presented broad spectrum fungicidal activities, especially for and . In this work, the design, synthesis, structure optimization, and mode of action of camalexin derivatives were carried out progressively. This work provides a reference for using defensive chemical compounds as novel pesticide lead compounds.
Topics: Antiviral Agents; Drug Design; Fungi; Indoles; Molecular Docking Simulation; Sesquiterpenes; Structure-Activity Relationship; Thiazoles; Tobacco Mosaic Virus; Phytoalexins
PubMed: 35179026
DOI: 10.1021/acs.jafc.1c07805 -
Molecules (Basel, Switzerland) Apr 2021The recently emerged COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has adversely affected the whole world. As a significant... (Review)
Review
The recently emerged COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has adversely affected the whole world. As a significant public health threat, it has spread worldwide. Scientists and global health experts are collaborating to find and execute speedy diagnostics, robust and highly effective vaccines, and therapeutic techniques to tackle COVID-19. The ocean is an immense source of biologically active molecules and/or compounds with antiviral-associated biopharmaceutical and immunostimulatory attributes. Some specific algae-derived molecules can be used to produce antibodies and vaccines to treat the COVID-19 disease. Algae have successfully synthesized several metabolites as natural defense compounds that enable them to survive under extreme environments. Several algae-derived bioactive molecules and/or compounds can be used against many diseases, including microbial and viral infections. Moreover, some algae species can also improve immunity and suppress human viral activity. Therefore, they may be recommended for use as a preventive remedy against COVID-19. Considering the above critiques and unique attributes, herein, we aimed to systematically assess algae-derived, biologically active molecules that could be used against this disease by looking at their natural sources, mechanisms of action, and prior pharmacological uses. This review also serves as a starting point for this research area to accelerate the establishment of anti-SARS-CoV-2 bioproducts.
Topics: Antiviral Agents; COVID-19; Carrageenan; Chlorophyta; Humans; Lectins; Phaeophyceae; Polysaccharides; Rhodophyta; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33917694
DOI: 10.3390/molecules26082134 -
International Journal of Pharmaceutics May 2022Unpredictable outbreaks due to respiratory viral infections emphasize the need for new drug delivery strategies to the entire respiratory tract. As viral attack is not...
Unpredictable outbreaks due to respiratory viral infections emphasize the need for new drug delivery strategies to the entire respiratory tract. As viral attack is not limited to a specific anatomic region, antiviral therapy that targets both the upper and lower respiratory tract would be most effective. This study aimed to formulate tamibarotene, a retinoid derivative previously reported to display broad-spectrum antiviral activity against influenza and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), as a novel dual particle size powder formulation that targets both the nasal cavity and the lung by a single route of intranasal administration. Spray freeze drying (SFD) and spray drying (SD) techniques were employed to prepare tamibarotene powder formulations, and cyclodextrin was used as the sole excipient to enhance drug solubility. With the employment of appropriate atomizing nozzles, particles of size above 10 μm and below 5 μm could be produced for nasal and lung deposition, respectively. The aerosol performance of the powder was evaluated using Next Generation Impactor (NGI) coupled with a glass expansion chamber and the powder was dispersed with a nasal powder device. By blending powder of two different particle sizes, a single powder formulation with dual aerosol deposition characteristic in both the nasal and pulmonary regions was produced. The aerosol deposition fractions in the nasal cavity and pulmonary region could be modulated by varying the powder mixing ratio. All dry powder formulations exhibited spherical structures, amorphous characteristics and improved dissolution profile as compared to the unformulated tamibarotene. Overall, a novel dual targeting powder formulation of tamibarotene exhibiting customizable aerosol deposition profile was developed. This exceptional formulation strategy can be adopted to deliver other antimicrobial agents to the upper and lower airways for the prevention and treatment of human respiratory infections.
Topics: Administration, Inhalation; Administration, Intranasal; Aerosols; Antiviral Agents; Dry Powder Inhalers; Humans; Lung; Particle Size; Powders; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35358643
DOI: 10.1016/j.ijpharm.2022.121704 -
Cepharanthine: a review of the antiviral potential of a Japanese-approved alopecia drug in COVID-19.Pharmacological Reports : PR Dec 2020Cepharanthine (CEP) is a naturally occurring alkaloid derived from Stephania cepharantha Hayata and demonstrated to have unique anti-inflammatory, antioxidative,... (Review)
Review
Cepharanthine (CEP) is a naturally occurring alkaloid derived from Stephania cepharantha Hayata and demonstrated to have unique anti-inflammatory, antioxidative, immunomodulating, antiparasitic, and antiviral properties. Its therapeutic potential as an antiviral agent has never been more important than in combating COVID-19 caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) virus. Cepharanthine suppresses nuclear factor-kappa B (NF-κB) activation, lipid peroxidation, nitric oxide (NO) production, cytokine production, and expression of cyclooxygenase; all of which are crucial to viral replication and inflammatory response. Against SARS-CoV-2 and homologous viruses, CEP predominantly inhibits viral entry and replication at low doses; and was recently identified as the most potent coronavirus inhibitor among 2406 clinically approved drug repurposing candidates in a preclinical model. This review critically analyzes and consolidates available evidence establishing CEP's potential therapeutic importance as a drug of choice in managing COVID-19 cases.
Topics: Animals; Anti-Inflammatory Agents; Antiviral Agents; Benzylisoquinolines; COVID-19; Drug Repositioning; Humans; Inflammation; Japan; SARS-CoV-2; Virus Replication; COVID-19 Drug Treatment
PubMed: 32700247
DOI: 10.1007/s43440-020-00132-z -
The Journal of Antimicrobial... Oct 2022Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiological agent of coronavirus disease 2019 (COVID-19) and a devastating worldwide health concern....
OBJECTIVES
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiological agent of coronavirus disease 2019 (COVID-19) and a devastating worldwide health concern. Development of safe and effective treatments is not only important for interventions during the current pandemic, but also for providing general treatment options moving forward. We have developed ensitrelvir, an antiviral compound that targets the 3C-like protease of SARS-CoV-2. In this study, a delayed-treatment mouse model was used to clarify the potential in vivo efficacy of ensitrelvir.
METHODS
Female BALB/cAJcl mice of different ages were infected with the SARS-CoV-2 gamma strain (hCoV-19/Japan/TY7-501/2021) or mouse-adapted SARS-CoV-2 MA-P10 and then 24 h post-infection orally administered various doses of ensitrelvir or vehicle. Viral titres and RNA levels in the lungs were quantified using VeroE6/TMPRSS2 cells and RT-qPCR, respectively. Body weight loss, survival, lung weight, cytokine/chemokine production, nucleocapsid protein expression and lung pathology were evaluated to investigate the in vivo efficacy of ensitrelvir.
RESULTS
Based on infectious viral titres and viral RNA levels in the lungs of infected mice, ensitrelvir reduced viral loads in a dose-dependent manner. The antiviral efficacy correlated with increased survival, reduced body weight loss, reduced pulmonary lesions and suppression of inflammatory cytokine/chemokine levels.
CONCLUSIONS
This was the first evaluation of the in vivo anti-SARS-CoV-2 efficacy of ensitrelvir in a delayed-treatment mouse model. In this model, ensitrelvir demonstrated high antiviral potential and suppressed lung inflammation and lethality caused by SARS-CoV-2 infection. The findings support the continued clinical development of ensitrelvir as an antiviral agent to treat patients with COVID-19.
Topics: Animals; Female; Mice; Antiviral Agents; Chemokines; Cytokines; Disease Models, Animal; Lung; SARS-CoV-2; Weight Loss; COVID-19 Drug Treatment
PubMed: 35914182
DOI: 10.1093/jac/dkac257 -
Viruses Aug 2018There are dozens of approved, investigational and experimental antiviral agents. Many of these agents cause serious side effects, which can only be revealed after drug... (Review)
Review
There are dozens of approved, investigational and experimental antiviral agents. Many of these agents cause serious side effects, which can only be revealed after drug administration. Identification of the side effects prior to drug administration is challenging. Here we describe an ex vivo approach for studying immuno- and neuro-modulatory properties of antiviral agents, which may be associated with potential side effects of these therapeutics. The current approach combines drug toxicity/efficacy tests and transcriptomics, which is followed by mRNA, cytokine and metabolite profiling. We demonstrated the utility of this approach with several examples of antiviral agents. We also showed that the approach can utilize different immune stimuli and cell types. It can also include other omics techniques, such as genomics and epigenomics, to allow identification of individual markers associated with adverse reactions to antivirals with immuno- and neuro-modulatory properties.
Topics: Antiviral Agents; Cytokines; Epigenomics; Gene Expression Profiling; Genomics; Humans; Immune System; Metabolomics; Nervous System; Precision Medicine; Systems Biology
PubMed: 30103549
DOI: 10.3390/v10080423 -
Current Opinion in Infectious Diseases Dec 2015The mainstay of antiviral therapy for the alpha-herpesviruses [herpes simplex virus (HSV)-1, HSV-2, and varicella zoster virus (VZV)] over the past 40 years has been the... (Review)
Review
PURPOSE OF REVIEW
The mainstay of antiviral therapy for the alpha-herpesviruses [herpes simplex virus (HSV)-1, HSV-2, and varicella zoster virus (VZV)] over the past 40 years has been the nucleoside analogues such as aciclovir. Although conventional antiviral therapy has reduced mortality in severe disease, novel agents are needed to address the emergence of resistance and toxicity associated with current second-line therapy. Treatment and prophylaxis of VZV and HSV reactivations remains a challenge.
RECENT FINDINGS
A number of compounds have recently been evaluated in human clinical trials, amongst them brincidofovir, an intracellularly acting derivative of cidofovir currently undergoing phase III trials. The helicase-primase inhibitors are a new class of antiviral agent and may circumvent resistance to existing agents. Amenamevir and pritelivir are two examples of these agents that have been evaluated clinically along with novel nucleoside analogues such as valomaciclovir and FV-100. Tenofovir, an agent used in HIV and hepatitis B therapy, may also have a role in the prevention of HSV-2 acquisition and reduce viral shedding.
SUMMARY
Although several novel antiviral agents have undergone clinical trials in recent years, all are yet to gain licensure. Brincidofovir appears to be the candidate with most promise for adoption into routine practice in the near future.
Topics: Antiviral Agents; Clinical Trials as Topic; Cytosine; Drug Discovery; Drug Evaluation; Drug Resistance, Viral; Herpes Simplex; Herpes Zoster; Humans; Microbial Sensitivity Tests; Organophosphonates; Treatment Outcome; Virus Replication
PubMed: 26524331
DOI: 10.1097/QCO.0000000000000211 -
Basic & Clinical Pharmacology &... Feb 2021The coronavirus responsible for COVID-19, SARS-CoV-2, utilizes a viral membrane spike protein for host cell entry. For the virus to engage in host membrane fusion,... (Review)
Review
The coronavirus responsible for COVID-19, SARS-CoV-2, utilizes a viral membrane spike protein for host cell entry. For the virus to engage in host membrane fusion, SARS-CoV-2 utilizes the human transmembrane surface protease, TMPRSS2, to cleave and activate the spike protein. Camostat mesylate, an orally available well-known serine protease inhibitor, is a potent inhibitor of TMPRSS2 and has been hypothesized as a potential antiviral drug against COVID-19. In vitro human cell and animal studies have shown that camostat mesylate inhibits virus-cell membrane fusion and hence viral replication. In mice, camostat mesylate treatment during acute infection with influenza, also dependent on TMPRSS2, leads to a reduced viral load. The decreased viral load may be associated with an improved patient outcome. Because camostat mesylate is administered as an oral drug, it may be used in outpatients as well as inpatients at all disease stages of SARS-CoV-2 infection if it is shown to be an effective antiviral agent. Clinical trials are currently ongoing to test whether this well-known drug could be repurposed and utilized to combat the current pandemic. In the following, we will review current knowledge on camostat mesylate mode of action, potential benefits as an antiviral agent and ongoing clinical trials.
Topics: Animals; Antiviral Agents; Drug Repositioning; Esters; Guanidines; Humans; Mice; Patient Safety; Serine Endopeptidases; Serine Proteinase Inhibitors; COVID-19 Drug Treatment
PubMed: 33176395
DOI: 10.1111/bcpt.13533