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Nature Communications Jul 2023Ensitrelvir, an oral antiviral agent that targets a SARS-CoV-2 main protease (3CLpro or Nsp5), is clinically useful against SARS-CoV-2 including its omicron variants....
Ensitrelvir, an oral antiviral agent that targets a SARS-CoV-2 main protease (3CLpro or Nsp5), is clinically useful against SARS-CoV-2 including its omicron variants. Since most omicron subvariants have reduced sensitivity to most monoclonal antibody therapies, SARS-CoV-2 resistance to other antivirals including main protease inhibitors such as ensitrelvir is a major public health concern. Here, repeating passages of SARS-CoV-2 in the presence of ensitrelvir revealed that the M49L and E166A substitutions in Nsp5 are responsible for reduced sensitivity to ensitrelvir. Both substitutions reduced in vitro virus growth in the absence of ensitrelvir. The combination of the M49L and E166A substitutions allowed the virus to largely evade the suppressive effect of ensitrelvir in vitro. The virus possessing Nsp5-M49L showed similar pathogenicity to wild-type virus, whereas the virus possessing Nsp5-E166A or Nsp5-M49L/E166A slightly attenuated. Ensitrelvir treatment of hamsters infected with the virus possessing Nsp5-M49L/E166A was ineffective; however, nirmatrelvir or molnupiravir treatment was effective. Therefore, it is important to closely monitor the emergence of ensitrelvir-resistant SARS-CoV-2 variants to guide antiviral treatment selection.
Topics: Animals; Cricetinae; COVID-19; SARS-CoV-2; Antiviral Agents
PubMed: 37454219
DOI: 10.1038/s41467-023-40018-1 -
Viruses Dec 2019Cytomegalovirus (CMV) is a threat to human health in the world, particularly for immunologically weak patients. CMV may cause opportunistic infections, congenital... (Review)
Review
Cytomegalovirus (CMV) is a threat to human health in the world, particularly for immunologically weak patients. CMV may cause opportunistic infections, congenital infections and central nervous system infections. CMV infections are difficult to treat due to their specific life cycles, mutation, and latency characteristic. Despite recent advances, current drugs used for treating active CMV infections are limited in their efficacy, and the eradication of latent infections is impossible. Current antiviral agents which target the UL54 DNA polymerase are restricted because of nephrotoxicity and viral resistance. CMV also cannot be prevented or eliminated with a vaccine. Fortunately, letermovir which targets the human CMV (HCMV) terminase complex has been recently approved to treat CMV infections in humans. The growing point is developing antiviral agents against both lytically and latently infected cells. The nucleic acid-based therapeutic approaches including the external guide sequences (EGSs)-RNase, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and transcription activator-like effector nucleases (TALENs) are being explored to remove acute and/or latent CMV infections. HCMV vaccine is being developed for prophylaxis. Additionally, adoptive T cell therapy (ACT) has been experimentally used to combate drug-resistant and recurrent CMV in patients after cell and/or organ transplantation. Developing antiviral agents is promising in this area to obtain fruitful outcomes and to have a great impact on humans for the therapy of CMV infections.
Topics: Antiviral Agents; CRISPR-Cas Systems; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Humans; Immunotherapy, Adoptive; Viral Vaccines; Virus Latency
PubMed: 31878068
DOI: 10.3390/v12010021 -
Molecules (Basel, Switzerland) Oct 2022A series of oxazinyl flavonoids were synthesized on the basis of flavone. The structures of all target compounds were characterized by H NMR, C NMR, and HRMS. The effect...
A series of oxazinyl flavonoids were synthesized on the basis of flavone. The structures of all target compounds were characterized by H NMR, C NMR, and HRMS. The effect of the different substituent on the N-position of oxazinyl flavonoids against tobacco mosaic virus (TMV) activities and plant pathogen activities was systematically investigated. In vivo anti-TMV activity showed that most of the compounds showed moderate-to-excellent antiviral activities against TMV at 500 μg/mL. Compounds , , -, and - showed better antiviral activities than ribavirin (a commercially available antiviral agent) and apigenin. In particular, compounds and even displayed slightly higher activities than ningnanmycin, which were expected to become new antiviral candidates. Antiviral mechanism research by molecular docking exhibited that compounds and could interact with TMV CP and inhibit virus assembly. Then, the antifungal activities of these compounds against six kinds of plant pathogenic fungi were tested, and the results showed that these oxazinyl flavonoids had broad-spectrum fungicidal activities. Compounds exhibited antifungal activity of up to 91% against and might become a candidate drug for new fungicides.
Topics: Antiviral Agents; Ribavirin; Fungicides, Industrial; Antifungal Agents; Structure-Activity Relationship; Flavonoids; Molecular Docking Simulation; Apigenin; Molecular Structure; Alkaloids; Tobacco Mosaic Virus; Fungi; Drug Design
PubMed: 36296469
DOI: 10.3390/molecules27206875 -
Pharmacology & Therapeutics May 2020Favipiravir has been developed as an anti-influenza drug and licensed as an anti-influenza drug in Japan. Additionally, favipiravir is being stockpiled for 2 million... (Review)
Review
Favipiravir has been developed as an anti-influenza drug and licensed as an anti-influenza drug in Japan. Additionally, favipiravir is being stockpiled for 2 million people as a countermeasure for novel influenza strains. This drug functions as a chain terminator at the site of incorporation of the viral RNA and reduces the viral load. Favipiravir cures all mice in a lethal influenza infection model, while oseltamivir fails to cure the animals. Thus, favipiravir contributes to curing animals with lethal infection. In addition to influenza, favipiravir has a broad spectrum of anti-RNA virus activities in vitro and efficacies in animal models with lethal RNA viruses and has been used for treatment of human infection with life-threatening Ebola virus, Lassa virus, rabies, and severe fever with thrombocytopenia syndrome. The best feature of favipiravir as an antiviral agent is the apparent lack of generation of favipiravir-resistant viruses. Favipiravir alone maintains its therapeutic efficacy from the first to the last patient in an influenza pandemic or an epidemic lethal RNA virus infection. Favipiravir is expected to be an important therapeutic agent for severe influenza, the next pandemic influenza strain, and other severe RNA virus infections for which standard treatments are not available.
Topics: Amides; Animals; Antiviral Agents; Humans; Influenza, Human; Pyrazines; RNA Virus Infections
PubMed: 32097670
DOI: 10.1016/j.pharmthera.2020.107512 -
Food and Environmental Virology Jun 2022The use of natural resources for the prevention and treatment of diseases considered fatal to humanity has evolved. Several medicinal plants have nutritional and... (Review)
Review
The use of natural resources for the prevention and treatment of diseases considered fatal to humanity has evolved. Several medicinal plants have nutritional and pharmacological potential in the prevention and treatment of viral infections, among them, turmeric, which is recognized for its biological properties associated with curcuminoids, mainly represented by curcumin, and found mostly in rhizomes. The purpose of this review was to compile the pharmacological activities of curcumin and its analogs, aiming at stimulating their use as a therapeutic strategy to treat infections caused by RNA genome viruses. We revisited its historical application as an anti-inflammatory, antioxidant, and antiviral agent that combined with low toxicity, motivated research against viruses affecting the population for decades. Most findings concentrate particularly on arboviruses, HIV, and the recent SARS-CoV-2. As one of the main conclusions, associating curcuminoids with nanomaterials increases solubility, bioavailability, and antiviral effects, characterized by blocking the entry of the virus into the cell or by inhibiting key enzymes in viral replication and transcription.
Topics: Antiviral Agents; Curcumin; Diarylheptanoids; Humans; RNA; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35352306
DOI: 10.1007/s12560-022-09514-3 -
Discovery Medicine 2021Remdesivir is a broad-spectrum antiviral agent. With the rapid spread of Coronavirus disease 2019 (COVID-19) globally, remdesivir is taking the spotlight for COVID-19...
Remdesivir is a broad-spectrum antiviral agent. With the rapid spread of Coronavirus disease 2019 (COVID-19) globally, remdesivir is taking the spotlight for COVID-19 treatment. Despite the promising signs of anti-CoV activity in several preclinical and clinical studies, more data of remdesivir in the treatment of COVID-19 is still needed for evaluating its efficacy.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Humans; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34965372
DOI: No ID Found -
Antiviral Research Jul 2022In addition to severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 has become the third... (Review)
Review
In addition to severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 has become the third deadly coronavirus that infects humans and causes the new coronavirus disease (COVID-19). COVID-19 has already caused more than six million deaths worldwide and it is likely the biggest pandemic of this century faced by mankind. Although many studies on SARS-CoV-2 have been conducted, a detailed understanding of SARS-CoV-2 and COVID-19 is still lacking. Animal models are indispensable for studying its pathogenesis and developing vaccines and antivirals. In this review, we analyze animal models of coronavirus infections and explore their applications on antivirals and vaccines.
Topics: Animals; Antiviral Agents; COVID-19; Middle East Respiratory Syndrome Coronavirus; Models, Animal; SARS-CoV-2; Viral Vaccines; COVID-19 Drug Treatment
PubMed: 35605699
DOI: 10.1016/j.antiviral.2022.105345 -
International Journal of Molecular... Oct 2022In this research, the synergistic antiviral effects of carbon nanotubes (CNTs) and metal oxides (MO) in the form of novel hybrid structures (MO-CNTs) are presented. Raw...
In this research, the synergistic antiviral effects of carbon nanotubes (CNTs) and metal oxides (MO) in the form of novel hybrid structures (MO-CNTs) are presented. Raw CNTs, Ni(OH), FeO and MnO, as well as Ni(OH)-CNT, FeO-CNT and MnO-CNT were explored in this study against MS2 bacteriophage, which was used as a virus surrogate. The nano particles were synthesized and characterized using field emission scanning electron microscopy (FESEM), energy-dispersive X-ray spectroscopy (EDS), transmission electron microscopy (TEM), particle size analysis, Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD). Kinetic parameters such as the LD (lethal dose to kill 50% of the population), T and T (time taken to kill 50% and 80% of the population), SGR (specific growth rate) and IRD (initial rate of deactivation of the population) were also studied to examine the antiviral efficacy of these nanomaterials. Among all the nanomaterials, Ni(OH)-CNT was the most effective antiviral agent followed by FeO-CNT, MnO-CNT, raw CNTs, Ni(OH), FeO and MnO. When comparing the metal oxide-CNTs to the raw CNTs, the average enhancement was 20.2%. The average antiviral activity enhancement of the MO-CNTs were between 50 and 54% higher than the MO itself. When compared to the raw CNTs, the average enhancement over all the MO-CNTs was 20.2%. The kinetic studies showed that the LD of Ni(OH)-CNT was the lowest (16µg/mL), which implies that it was the most toxic of all the compounds studied. The LD of Ni(OH), FeO and MnO were 17.3×, 14.5× and 10.8× times greater than their corresponding hybrids with the CNTs. The synergistic mechanism involved the entrapment of phage viruses by the nano structured CNTs leading to structural damage along with toxicity to phage from the release of MO ions. The metal oxide-CNT nano hybrids developed in this project are promising candidates in applications such as antiviral coatings, nanocomposites, adsorbents and as components of personal protection gears.
Topics: Antiviral Agents; Kinetics; Manganese Compounds; Nanotubes, Carbon; Oxides
PubMed: 36233260
DOI: 10.3390/ijms231911957 -
Chemical Biology & Drug Design Jun 2022Nucleoside analogs are the backbone of antiviral therapies. Drugs from this class undergo processing by host or viral kinases to form the active nucleoside triphosphate...
Nucleoside analogs are the backbone of antiviral therapies. Drugs from this class undergo processing by host or viral kinases to form the active nucleoside triphosphate species that selectively inhibits the viral polymerase. It is the central hypothesis that the nucleoside triphosphate analog must be a favorable substrate for the viral polymerase and the nucleoside precursor must be a satisfactory substrate for the host kinases to inhibit viral replication. Herein, free energy perturbation (FEP) was used to predict substrate affinity for both host and viral enzymes. Several uridine 5'-monophosphate prodrug analogs known to inhibit hepatitis C virus (HCV) were utilized in this study to validate the use of FEP. Binding free energies to the host monophosphate kinase and viral RNA-dependent RNA polymerase (RdRp) were calculated for methyl-substituted uridine analogs. The 2'-C-methyl-uridine and 4'-C-methyl-uridine scaffolds delivered favorable substrate binding to the host kinase and HCV RdRp that were consistent with results from cellular antiviral activity in support of our new approach. In a prospective evaluation, FEP results suggest that 2'-C-dimethyl-uridine scaffold delivered favorable monophosphate and triphosphate substrates for both host kinase and HCV RdRp, respectively. Novel 2'-C-dimethyl-uridine monophosphate prodrug was synthesized and exhibited sub-micromolar inhibition of HCV replication. Using this novel approach, we demonstrated for the first time that nucleoside analogs can be rationally designed that meet the multi-target requirements for antiviral activity.
Topics: Antiviral Agents; Hepacivirus; Hepatitis C; Humans; Nucleosides; Nucleotides; Prodrugs; RNA-Dependent RNA Polymerase; Uridine; Viral Nonstructural Proteins; Virus Replication
PubMed: 35313085
DOI: 10.1111/cbdd.14042 -
Molecules (Basel, Switzerland) Mar 2023Pesticides are essential for the development of agriculture. It is urgent to develop green, safe and efficient pesticides. Bisindole alkaloids have unique and concise...
Pesticides are essential for the development of agriculture. It is urgent to develop green, safe and efficient pesticides. Bisindole alkaloids have unique and concise structures and broad biological activities, which make them an important leading skeleton in the creation of new pesticides. In this work, we synthesized bisindole alkaloid barakacin in a simple seven-step process, and simultaneously designed and synthesized a series of its derivatives. Biological activity research indicated that most of these compounds displayed good antiviral activities against tobacco mosaic virus (TMV). Among them, compound exerted a superior inhibitory effect in comparison to commercially available antiviral agent ribavirin, and could be expected to become a novel antiviral candidate. Molecular biology experiments and molecular docking research found that the potential target of compound was TMV coat protein (CP). These compounds also showed broad-spectrum anti-fungal activities against seven kinds of plant fungi.
Topics: Antiviral Agents; Structure-Activity Relationship; Molecular Docking Simulation; Fungicides, Industrial; Ribavirin; Tobacco Mosaic Virus; Alkaloids; Drug Design
PubMed: 37049795
DOI: 10.3390/molecules28073032