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Scientific Reports Feb 2023Remdesivir (GS-5734; VEKLURY) is a single diastereomer monophosphoramidate prodrug of an adenosine analog (GS-441524). Remdesivir is taken up by target cells and...
Remdesivir (GS-5734; VEKLURY) is a single diastereomer monophosphoramidate prodrug of an adenosine analog (GS-441524). Remdesivir is taken up by target cells and metabolized in multiple steps to form the active nucleoside triphosphate (GS-443902), which acts as a potent inhibitor of viral RNA-dependent RNA polymerases. Remdesivir and GS-441524 have antiviral activity against multiple RNA viruses. Here, we expand the evaluation of remdesivir's antiviral activity to members of the families Flaviviridae, Picornaviridae, Filoviridae, Orthomyxoviridae, and Hepadnaviridae. Using cell-based assays, we show that remdesivir can inhibit infection of flaviviruses (such as dengue 1-4, West Nile, yellow fever, Zika viruses), picornaviruses (such as enterovirus and rhinovirus), and filoviruses (such as various Ebola, Marburg, and Sudan virus isolates, including novel geographic isolates), but is ineffective or is significantly less effective against orthomyxoviruses (influenza A and B viruses), or hepadnaviruses B, D, and E. In addition, remdesivir shows no antagonistic effect when combined with favipiravir, another broadly acting antiviral nucleoside analog, and has minimal interaction with a panel of concomitant medications. Our data further support remdesivir as a broad-spectrum antiviral agent that has the potential to address multiple unmet medical needs, including those related to antiviral pandemic preparedness.
Topics: Humans; Antiviral Agents; Adenosine Monophosphate; Alanine; Hemorrhagic Fever, Ebola; Filoviridae; Zika Virus; Zika Virus Infection
PubMed: 36823196
DOI: 10.1038/s41598-023-29517-9 -
Molecules (Basel, Switzerland) Feb 2023L. is used to cure many types of fever in traditional medicine. This study aims to explore the antiviral activity of the lipophilic fraction of the stem of (LFOB)...
L. is used to cure many types of fever in traditional medicine. This study aims to explore the antiviral activity of the lipophilic fraction of the stem of (LFOB) against dengue virus (DENV) and chikungunya virus (CHIKV). The LFOB was analyzed using GC-FID and GC-MS. The antiviral activity of LFOB was studied using the Vero CCL-81 cell line. The cytotoxicity assay was performed using 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT). In vitro antiviral activity and FFU assay were used to determine and confirm antiviral activity against DENV and CHIKV. Twenty-six compounds were identified in LFOB using GC/MS. The most abundant compounds were -sitosterol (22.9%), stigmasterol (18.7%), and campesterol (12.9%). Significant reduction in DENV titre was observed under pre- and post-infection treatment conditions at a concentration of 3.125 µg/mL, but no anti-CHIKV activity was observed. Our earlier and the present AutoDock-Vina-based in silico docking study revealed that -sitosterol and stigmasterol could form strong interactions with the DENV E glycoprotein and DENV RdRp domain, respectively. Our findings suggest that LFOB can inhibit DENV infection and might act as a potent prophylactic/therapeutic agent against DENV-2. In silico results suggested that -sitosterol and stigmasterol may block the viral entry by inhibiting the fusion process and viral replication respectively.
Topics: Ocimum basilicum; Stigmasterol; Dengue Virus; Antiviral Agents; Cell Line; Chikungunya virus
PubMed: 36771120
DOI: 10.3390/molecules28031446 -
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) May 2023Compounds with acylhydrazone fragments contain amide and imine groups that can act as electron donors and acceptors, so they are easier to bind to biological targets and...
Compounds with acylhydrazone fragments contain amide and imine groups that can act as electron donors and acceptors, so they are easier to bind to biological targets and thus generally exhibit significant biological activity. In this work, acylhydrazone fragments were introduced to the C-14 or C-11 position of matrine, a natural alkaloid, aiming to enhance their biological activities. The result of this bioassay showed that many synthesized compounds exhibited excellent anti-virus activity against the tobacco mosaic virus (TMV). Seventeen out of 25 14-acylhydrazone matrine derivatives and 17 out of 20 11-butanehydrazone matrine derivatives had a higher inhibitory activity against TMV than the commercial antiviral agent Ribavirin (the in vitro activity, in vivo inactivation, curative and protection activities at 500 µg/mL were 40.9, 36.5 ± 0.9, 38.0 ± 1.6 and 35.1 ± 2.2%, respectively), and four 11-butanehydrazone matrine derivatives even had similar to or higher activity than the most efficient antiviral agent Ningnanmycin (55.4, 57.8 ± 1.4, 55.3 ± 0.5 and 60.3 ± 1.2% at 500 µg/mL for the above four test modes). Among them, the -benzyl-11-butanehydrazone of matrine formed with 4-bromoindole-3-carboxaldehyde exhibited the best anti-TMV activity (65.8, 71.8 ± 2.8, 66.8 ± 1.3 and 69.5 ± 3.1% at 500 µg/mL; 29, 33.5 ± 0.7, 24.1 ± 0.2 and 30.3 ± 0.6% at 100 µg/mL for the above four test modes), deserving further investigation as an antiviral agent. Other than these, the two series of acylhydrazone-containing matrine derivatives were evaluated for their insecticidal and fungicidal activities. Several compounds were found to have good insecticidal activities against diamondback moth () and mosquito larvae (), showing broad biological activities.
Topics: Animals; Molecular Structure; Structure-Activity Relationship; Matrines; Insecticides; Tobacco Mosaic Virus; Moths; Antiviral Agents; Drug Design
PubMed: 37241904
DOI: 10.3390/molecules28104163 -
British Journal of Pharmacology Feb 2021Respiratory syncytial virus (RSV) is an important infectious agent in infants and young children. In most cases, RSV infection only causes mild disease, but in some, it... (Review)
Review
Respiratory syncytial virus (RSV) is an important infectious agent in infants and young children. In most cases, RSV infection only causes mild disease, but in some, it requires invasive ventilation. Although antiviral drugs are obvious candidates to treat viral illness, and some have shown antiviral effects in humans, antivirals such as GS-5806, ALX-0171 and ALS-8176 have not yet met their expectations. Since the inappropriate or dysregulated immune response against RSV leads to harmful immune pathology, a robust immune cascade is probably underway by the time patients reach the hospital. RSV infection is associated with a strong neutrophil influx into the airway. It not clear if these cells contribute to antiviral defence or to lung pathology. This article discusses the protective and harmful roles of neutrophils during RSV infection and provides an overview of mechanisms by which neutrophil function could be targeted to prevent tissue injury and preserve homeostasis.
Topics: Antiviral Agents; Child; Child, Preschool; Humans; Lung; Neutrophils; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human
PubMed: 33169387
DOI: 10.1111/bph.15318 -
Cytokine Oct 2021Interferons have prominent roles in various pathophysiological conditions, mostly related to inflammation. Interferon-gamma (IFNγ) was, initially discovered as a potent... (Review)
Review
Interferons have prominent roles in various pathophysiological conditions, mostly related to inflammation. Interferon-gamma (IFNγ) was, initially discovered as a potent antiviral agent, over 50 years ago, and has recently garnered renewed interest as a promising factor involved in both innate and adaptive immunity. When new disease epidemics appear such as SARS-CoV (severe acute respiratory syndrome coronavirus), MERS-CoV (Middle East respiratory syndrome coronavirus), IAV (Influenza A virus), and in particular the current SARS-CoV-2 pandemic, it is especially timely to review the complexity of immune system responses to viral infections. Here we consider the controversial roles of effectors like IFNγ, discussing its actions in immunomodulation and immunotolerance. We explore the possibility that modulation of IFNγ could be used to influence the course of such infections. Importantly, not only could endogenous expression of IFNγ influence the outcome, there are existing IFNγ therapeutics that can readily be applied in the clinic. However, our understanding of the molecular mechanisms controlled by IFNγ suggests that the exact timing for application of IFNγ-based therapeutics could be crucial: it should be earlier to significantly reduce the viral load and thus decrease the overall severity of the disease.
Topics: Adaptive Immunity; Antiviral Agents; COVID-19; Humans; Immune Tolerance; Immunity, Innate; Interferon-gamma; Receptors, Interferon; SARS-CoV-2; Signal Transduction; COVID-19 Drug Treatment
PubMed: 34242899
DOI: 10.1016/j.cyto.2021.155637 -
European Journal of Medicinal Chemistry Oct 2023The major severe complications linked to Zika virus (ZIKV) cause the global public health problems, including microcephaly and other congenital abnormalities in...
The major severe complications linked to Zika virus (ZIKV) cause the global public health problems, including microcephaly and other congenital abnormalities in newborns, and Guillain-Barré syndrome, meningoencephalitis, multi-organ failure in adults. However, neither approved vaccines nor drugs are available for ZIKV. In this study, we describe the design, synthesis and the anti-ZIKV activities of a series of anthraquinone analogs. Most of the newly synthesized compounds demonstrated moderate to excellent potency against ZIKV. Among all, compound 22, showed the most potent anti-ZIKV activity (EC value from 1.33 μM to 5.72 μM) with low cytotoxicity (CC>50 μM) in multiple cellular model. Importantly, 22 significantly improved the survival of ZIKV-infected mice (Ifnar1), alleviated ZIKV-associated pathological damages and suppressed the excessive inflammatory response and pyroptosis induced by ZIKV in vivo and in vitro. Furthermore, the molecular docking simulation analysis and the surface plasmon resonance results demonstrated the direct binding between 22 and ZIKV RdRp, and the mechanistic study revealed that 22 suppressed viral RNA synthesis by ZIKV NS5 in cells. Taken together, this study highlights that 22 may be a novel anti-ZIKV drug candidate and provides treatment options for ZIKV-associated diseases.
Topics: Animals; Mice; Zika Virus; Antiviral Agents; Molecular Docking Simulation; Virus Replication; Zika Virus Infection
PubMed: 37421888
DOI: 10.1016/j.ejmech.2023.115620 -
Molecules (Basel, Switzerland) Oct 2022The Omicron variant (B.529) of COVID-19 caused disease outbreaks worldwide because of its contagious and diverse mutations. To reduce these outbreaks, therapeutic drugs... (Review)
Review
The Omicron variant (B.529) of COVID-19 caused disease outbreaks worldwide because of its contagious and diverse mutations. To reduce these outbreaks, therapeutic drugs and adjuvant vaccines have been applied for the treatment of the disease. However, these drugs have not shown high efficacy in reducing COVID-19 severity, and even antiviral drugs have not shown to be effective. Researchers thus continue to search for an effective adjuvant therapy with a combination of drugs or vaccines to treat COVID-19 disease. We were motivated to consider melatonin as a defensive agent against SARS-CoV-2 because of its various unique properties. Over 200 scientific publications have shown the significant effects of melatonin in treating diseases, with strong antioxidant, anti-inflammatory, and immunomodulatory effects. Melatonin has a high safety profile, but it needs further clinical trials and experiments for use as a therapeutic agent against the Omicron variant of COVID-19. It might immediately be able to prevent the development of severe symptoms caused by the coronavirus and can reduce the severity of the infection by improving immunity.
Topics: Humans; SARS-CoV-2; Melatonin; Antioxidants; Antiviral Agents; COVID-19 Drug Treatment
PubMed: 36296527
DOI: 10.3390/molecules27206934 -
Infection Jun 2021COVID-19 is an infectious disease caused by a novel β-coronavirus, belonging to the same subgenus as the Severe Acute Respiratory Syndrome (SARS) virus. Remdesivir, an... (Review)
Review
COVID-19 is an infectious disease caused by a novel β-coronavirus, belonging to the same subgenus as the Severe Acute Respiratory Syndrome (SARS) virus. Remdesivir, an investigational broad-spectrum antiviral agent has previously demonstrated in vitro activity against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and in vivo efficacy against other related coronaviruses in animal models. Its safety profile has been tested in a compassionate use setting for patients with COVID-19. The current therapeutic studies demonstrate clinical effectiveness of remdesivir in COVID-19 patients by shortening time to clinical recovery, and hospital stay. In this review, we critically analyze the current evidence of remdesivir against COVID-19 and dissect the aspects over its safety and efficacy. Based on existing data, remdesivir can be regarded as a potential therapeutic agent against COVID-19. Further large-scale, randomized placebo-controlled clinical trials are, however, awaited to validate these findings.
Topics: Adenosine Monophosphate; Alanine; Animals; Antiviral Agents; COVID-19; Humans; SARS-CoV-2; Time Factors; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 33389708
DOI: 10.1007/s15010-020-01557-7 -
Molecules (Basel, Switzerland) Apr 2022Since COVID-19 has affected global public health, there has been an urgency to find a solution to limit both the number of infections, and the aggressiveness of the... (Review)
Review
Since COVID-19 has affected global public health, there has been an urgency to find a solution to limit both the number of infections, and the aggressiveness of the disease once infected. The main characteristic of this infection is represented by a strong alteration of the immune system which, day by day, increases the risk of mortality, and can lead to a multiorgan dysfunction. Because nutritional profile can influence patient's immunity, we focus our interest on resveratrol, a polyphenolic compound known for its immunomodulating and anti-inflammatory properties. We reviewed all the information concerning the different roles of resveratrol in COVID-19 pathophysiology using PubMed and Scopus as the main databases. Interestingly, we find out that resveratrol may exert its role through different mechanisms. In fact, it has antiviral activity inhibiting virus entrance in cells and viral replication. Resveratrol also improves autophagy and decreases pro-inflammatory agents expression acting as an anti-inflammatory agent. It regulates immune cell response and pro-inflammatory cytokines and prevents the onset of thrombotic events that usually occur in COVID-19 patients. Since resveratrol acts through different mechanisms, the effect could be enhanced, making a totally natural agent particularly effective as an adjuvant in anti COVID-19 therapy.
Topics: Anti-Inflammatory Agents; Antiviral Agents; Dietary Supplements; Humans; Resveratrol; COVID-19 Drug Treatment
PubMed: 35458574
DOI: 10.3390/molecules27082376