scholarly journals Development of Novel Anti-influenza Thiazolides with Relatively Broad-Spectrum Antiviral Potentials

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Lei Zhao ◽  
Yunzheng Yan ◽  
Qingsong Dai ◽  
Xingzhou Li ◽  
Ke Xu ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Broad Spectrum ◽  
Late Phase ◽  
Influenza Virus Infection ◽  
Oseltamivir Carboxylate ◽  
Cellular Genes ◽  
Action Analysis ◽  
Antiviral Activities ◽  
Resistant Strains ◽  
Entity Discovery

ABSTRACT Seasonal and pandemic influenza causes 650,000 deaths annually in the world. The emergence of drug resistance to specific anti-influenza virus drugs such as oseltamivir and baloxavir marboxil highlights the urgency of novel anti-influenza chemical entity discovery. In this study, we report a series of novel thiazolides derived from an FDA-approved drug, nitazoxanide, with antiviral activity against influenza and a broad range of viruses. The preferred candidates 4a and 4d showed significantly enhanced anti-influenza virus potentials, with 10-fold improvement compared to results with nitazoxanide, and were effective against a variety of influenza virus subtypes including oseltamivir-resistant strains. Notably, the combination using compounds 4a/4d and oseltamivir carboxylate or zanamivir displayed synergistic antiviral effects against oseltamivir-resistant strains. Mode-of-action analysis demonstrated that compounds 4a/4d acted at the late phase of the viral infection cycle through inhibiting viral RNA transcription and replication. Further experiments showed that treatment with compounds 4a/4d significantly inhibited influenza virus infection in human lung organoids, suggesting the druggability of the novel thiazolides. In-depth transcriptome analysis revealed a series of upregulated cellular genes that may contribute to the antiviral activities of 4a/4d. Together, the results of our study indicated the direction to optimize nitazoxanide as an anti-influenza drug and discovered two candidates with novel structures, compounds 4a/4d, that have relatively broad-spectrum antiviral potentials.

scholarly journals A recombinant protein containing influenza viral conserved epitopes and superantigen induces broad-spectrum protection

2021 ◽  
Author(s):  
Yansheng Li ◽  
Mingkai Xu ◽  
Yongqiang Li ◽  
Wu Gu ◽  
Gulinare Halimu ◽  
...  
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
Recombinant Protein ◽  
Broad Spectrum ◽  
Influenza Pandemic ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Lung Damage ◽  
Potential Candidate ◽  
Universal Vaccine

Influenza pandemic poses public health threats annually for lacking vaccine which provides cross-protection against novel and emerging influenza viruses. Combining conserved antigens inducing cross-protective antibody response with epitopes activating cross-protective cytotoxic T-cells would offer an attractive strategy for developing universal vaccine. In this study, we constructed a recombinant protein NMHC consisting of influenza viral conserved epitopes and superantigen fragment. NMHC promoted the mature of bone marrow-derived dendritic cells and induced CD4+ T cells to differentiate into Th1, 32 Th2 and Th17 subtypes. Mice vaccinated with NMHC produced high level of immunoglobulins which cross-bound to HA fragments from six influenza virus subtypes with high antibody titers. Anti-NMHC serum showed potent hemagglutinin inhibition effects to highly divergent group 1 (H1 subtypes) and group 2 (H3 subtype) influenza virus strains. And purified anti-NMHC antibodies could bind to multiple HAs with high affinities. NMHC vaccination effectively protected the mice from infection and lung damage challenged by two subtypes of H1N1 influenza virus. Moreover, NMHC vaccination elicited CD4+ and CD8+ T-cell responses to clear the virus from infected tissue and prevent virus spreading. In conclusion, this study provided proof of concept for triggering both B cells and T cells immune responses against multiple influenza virus infection, and NMHC may be a potential candidate of universal broad-spectrum vaccine for various influenza virus prevention and therapy.

scholarly journals Discovery of Allopregnanolone Against Influenza Virus With Broad Spectrum in Vitro

2021 ◽  
Author(s):  
yuqi Wang ◽  
Yanyan Wang ◽  
Hong Cao
Keyword(s):  
Natural Products ◽  
Influenza Virus ◽  
Viral Replication ◽  
Broad Spectrum ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Wild Type Virus ◽  
Dependent Manner ◽  
Viral Yield

Abstract Background: Influenza virus infection with seasonal or occasional but devastating morbidity and mortality, is a severe threat to public health. The frequent emergence of resistant viral strains limited application of current antivirals and posing an urgent need for novel antiviral therapies. Natural products offered a broad prospect in the screening and development of new influenza inhibitors.Methods: In this research, a high-throughput antiviral screening for 891 natural products was performed based on a recombinant reporter influenza A virus. According to the cytotoxicity assay and dose-response relationship, alloprogesterone (ALLO), as the positive hit was selected, and verified by viral titer reduction assay and immunofluorescence using a wild-type virus. Followingly, we explored its antiviral potency of counteracting with IAV and IBV, and preliminary investigated the mechanism of ALLO through time-of-addition assay and mini-replicon system.Results: Under the criteria of 80% inhibition and 70% cell viability, ALLO was screened out and confirmed antiviral activity in varied cells. The inhibitory effect of ALLO against influenza virus with a dose-dependent manner and significantly reduced viral yield of five different influenza viruses in the presence of 40 µM ALLO, including oseltamivir-resistant virus. Moreover, ALLO exhibited no influence on IAV entry or release during the viral replication cycle, but obviously interfered with the genome replication regarding post-infection 2 hrs to 6 hrs, which is consistent with the evidence of decreased polymerase activity.Conclusions: In summary, we firstly identified a new pharmacological activity of ALLO, as a broad spectrum inhibitor for treatment influenza infections, targeting viral replication stage and possessing great value of further development.

Antiviral Effect of Gingyo-San, a Traditional Chinese Herbal Medicine, on Influenza A2Virus Infection in Mice

1999 ◽  
Vol 27 (01) ◽  
pp. 53-62 ◽  
Author(s):  
Makiko Kobayashi ◽  
Stephen M. Davis ◽  
Tokuichiro Utsunomiya ◽  
Richard B. Pollard ◽  
Fujio Suzuki
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Mdck Cells ◽  
Influenza Virus Infection ◽  
Antiviral Agent ◽  
Antiviral Effect ◽  
Traditional Chinese Herbal Medicine ◽  
Antiviral Activities ◽  
The Common

Gingyo-san is a crude drug containing extracts from 7 medicinal plants and fermented soybeans in a specific ratio. It has been used clinically in China as a therapeutic agent for the common cold. In the present study, we examined the antiviral effect of this agent on influenza virus infection in mice. Gingyo-san and its components were administered orally to mice 1 day before, then 1 and 4, days after the inhalation of a mouse-adopted strain of influenza A2(H2N2) virus. After infection with a 10 LD50of the virus, 100% of mice treated with 10 mg/kg of the agent survived as compared with a 0% survival of control mice treated with saline. Also, the mean survival days were ncreased and consolidation scores were decreased in treated mice as compared with those of control mice. Two components contained in the agent, extracts from Glycyrrhizae radix and Arctii fructus, expressed antiviral activities in mice infected with influenza virus. However, in vitro growth of influenza virus in MDCK cells or viability of the virus was not affected by these extracts or Gingyo-san. From these results Gingyo-san was shown to be an antiviral agent in mice infected with a lethal amount of a mouse-adopted strain of influenza A2virus.

scholarly journals Design and Synthesis of Quinolizidine Derivatives as Influenza Virus and HIV-1 Inhibitors

2020 ◽  
Vol 28 ◽  
Author(s):  
Zhao Dang ◽  
Lei Zhu ◽  
Lan Xie ◽  
Kuo-Hsiung Lee ◽  
Faisal Malik ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza Virus Infection ◽  
Antiviral Compound ◽  
Replication Assay ◽  
Design And Synthesis ◽  
Influenza Activity ◽  
Antiviral Activities ◽  
Activity Groups ◽  
Anti Hiv ◽  
Hiv 1

Background: We have previously reported that a quinolizidine natural product, aloperine, and its analogs can inhibit influenza virus and/or HIV-1 at low µM concentrations. Objective: The main goal of this study was to further optimize aloperine for improved anti–influenza virus activity. Methods: Structural modifications have been focused on the N12 position of aloperine scaffold. Conventional chemical synthesis was used to obtain derivatives with improved antiviral activities. The anti-HIV and anti-influenza virus activities of the synthesized compounds were determined using an MT4 cell-based HIV-1 replication assay and an anti-influenza virus infection of MDCK cell assay, respectively. Results: Aloperine derivatives can be classified into three activity groups: those that exhibit anti-HIV activity only, anti– influenza virus only, or activity against both viruses. Aloperine optimized for potent anti-influenza activity often lost antiHIV-1 activity, and vice versa. Compound 19 inhibited influenza virus PR8 replication with an IC50 of 0.091 µM, which is approximately 160- and 60-fold more potent than aloperine and the previously reported aloperine derivative compound 3, respectively. Conclusion: The data suggest that aloperine is a privileged scaffold that can be modified to become a selective antiviral compound with markedly improved potency against influenza virus or HIV-1.

scholarly journals Comparison of the Anti-Influenza Virus Activity of RWJ-270201 with Those of Oseltamivir and Zanamivir

2001 ◽  
Vol 45 (4) ◽  
pp. 1162-1167 ◽  
Author(s):  
S. Bantia ◽  
C. D. Parker ◽  
S. L. Ananth ◽  
L. L. Horn ◽  
K. Andries ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Oral Administration ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Influenza B ◽  
Significant Protection ◽  
Oseltamivir Carboxylate ◽  
Structure Based Drug Design ◽  
Influenza Virus Neuraminidase

ABSTRACT We have recently reported an influenza virus neuraminidase inhibitor, RWJ-270201 (BCX-1812), a novel cyclopentane derivative discovered through structure-based drug design. In this paper, we compare the potency of three compounds, RWJ-270201, oseltamivir, and zanamivir, against neuraminidase enzymes from various subtypes of influenza. RWJ-270201 effectively inhibited all tested influenza A and influenza B neuraminidases in vitro, with 50% inhibitory concentrations of 0.09 to 1.4 nM for influenza A neuraminidases and 0.6 to 11 nM for influenza B neuraminidases. These values were comparable to or lower than those for oseltamivir carboxylate (GS4071) and zanamivir (GG167). RWJ-270201 demonstrated excellent selectivity (>10,000-fold) for influenza virus neuraminidase over mammalian, bacterial, or other viral neuraminidases. Oral administration of a dosage of 1 mg/kg of body weight/day of RWJ-270201 for 5 days (beginning 4 h preinfection) showed efficacy in the murine model of influenza virus infection as determined by lethality and weight loss protection. RWJ-270201 administered intranasally at 0.01 mg/kg/day in the murine influenza model demonstrated complete protection against lethality, whereas oseltamivir carboxylate and zanamivir at the same dose demonstrated only partial protection. In the delayed-treatment murine influenza model, oral administration of a 10-mg/kg/day dose of RWJ-270201 or oseltamivir (GS4104, a prodrug of GS4071) at 24 h postinfection showed significant protection against lethality (P < 0.001 versus control). However, when the treatment was delayed for 48 h, no significant protection was observed in either drug group. No drug-related toxicity was observed in mice receiving 100 mg/kg/day of RWJ-270201 for 5 days. These efficacy and safety profiles justify further consideration of RWJ-270201 for the treatment and prevention of human influenza.

scholarly journals Oseltamivir-Ribavirin Combination Therapy for Highly Pathogenic H5N1 Influenza Virus Infection in Mice

2008 ◽  
Vol 52 (11) ◽  
pp. 3889-3897 ◽  
Author(s):  
Natalia A. Ilyushina ◽  
Alan Hay ◽  
Neziha Yilmaz ◽  
Adrianus C. M. Boon ◽  
Robert G. Webster ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza Virus Infection ◽  
Antiviral Effect ◽  
Influenza Viruses ◽  
Oseltamivir Carboxylate ◽  
Highly Pathogenic ◽  
H5n1 Influenza ◽  
Pathogenic H5n1

ABSTRACT We studied the effects of a neuraminidase inhibitor (oseltamivir) and an inhibitor of influenza virus polymerases (ribavirin) against two highly pathogenic H5N1 influenza viruses. In vitro, A/Vietnam/1203/04 virus (clade 1) was highly susceptible to oseltamivir carboxylate (50% inhibitory concentration [IC50] = 0.3 nM), whereas A/Turkey/15/06 virus (clade 2.2) had reduced susceptibility (IC50 = 5.5 nM). In vivo, BALB/c mice were treated with oseltamivir (1, 10, 50, or 100 mg/kg of body weight/day), ribavirin (37.5, 55, or 75 mg/kg/day), or the combination of both drugs for 8 days, starting 4 h before virus inoculation. Monotherapy produced a dose-dependent antiviral effect against the two H5N1 viruses in vivo. Three-dimensional analysis of the drug-drug interactions revealed that oseltamivir and ribavirin interacted principally in an additive manner, with several exceptions of marginal synergy or marginal antagonism at some concentrations. The combination of ribavirin at 37.5 mg/kg/day and oseltamivir at 1 mg/kg/day and the combination of ribavirin at 37.5 mg/kg/day and oseltamivir at 10 mg/kg/day were synergistic against A/Vietnam/1203/04 and A/Turkey/15/06 viruses, respectively. These optimal oseltamivir-ribavirin combinations significantly inhibited virus replication in mouse organs, prevented the spread of H5N1 viruses beyond the respiratory tract, and abrogated the cytokine response (P < 0.01). Importantly, we observed clear differences between the efficacies of the drug combinations against two H5N1 viruses: higher doses were required for the protection of mice against A/Turkey/15/06 virus than for the protection of mice against A/Vietnam/1203/04 virus. Our preliminary results suggest that oseltamivir-ribavirin combinations can have a greater or lesser antiviral effect than monotherapy, depending on the H5N1 virus and the concentrations used.

Glycyrrhizin, an active component of licorice roots, reduces morbidity and mortality of mice infected with lethal doses of influenza virus.

1997 ◽  
Vol 41 (3) ◽  
pp. 551-556 ◽  
Author(s):  
T Utsunomiya ◽  
M Kobayashi ◽  
R B Pollard ◽  
F Suzuki
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
Active Component ◽  
Influenza Virus Infection ◽  
Experimental Period ◽  
Antiviral Effect ◽  
Ifn Gamma ◽  
Antiviral Activities ◽  
Lethal Doses

The antiviral effect of glycyrrhizin (GR), an active component of licorice roots, was investigated in mice infected with influenza virus A2 (H2N2). When mice that had been exposed to 10 50% lethal doses of the virus were treated intraperitoneally with 10 mg of GR per kg of body weight 1 day before infection and 1 and 4 days postinfection, all of the mice survived over the 21-day experimental period. At the end of this period, the mean survival time (in days) for control mice treated with saline was 10.5 days, and there were no survivors. The grade of pulmonary consolidations and the virus titers in the lung tissues of infected mice treated with GR were significantly lower than those in the lung tissues of infected mice treated with saline. GR did not show any effects on the viability or replication of influenza virus A2 in vitro. When splenic T cells from GR-treated mice were adoptively transferred to mice exposed to influenza virus, 100% of the recipients survived, compared to 0% survival for recipient mice inoculated with naive T cells or splenic B cells and macrophages from GR-treated mice. In addition, the antiviral activities of GR on influenza virus infection in mice were not demonstrated when it was administered to infected mice in combination with anti-gamma interferon (anti-IFN-gamma) monoclonal antibody. These results suggest that GR may protect mice exposed to a lethal amount of influenza virus through the stimulation of IFN-gamma production by T cells, because T cells have been shown to be producer cells of IFN-gamma stimulated with the compound.

Influenza Virus in Community-Acquired Pneumonia: Current Understanding and Knowledge Gaps

2020 ◽  
Vol 41 (04) ◽  
pp. 555-567
Author(s):  
Jiuyang Xu ◽  
Jiapei Yu ◽  
Luning Yang ◽  
Fei Zhou ◽  
Hui Li ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza Pandemic ◽  
Late Phase ◽  
Influenza Virus Infection ◽  
Community Acquired Pneumonia ◽  
Detection Methods ◽  
Knowledge Gaps ◽  
Viral Pathogen ◽  
Inflammatory Phase

AbstractInfluenza virus infection poses a heavy burden on global health and economics. With the advancement in viral pathogen detection methods, the role of virus infection in community-acquired pneumonia has been increasingly recognized. The disease spectrum of influenza ranges from asymptomatic infection to severe or even fatal illness. Progress has been made in recent years to identify risk factors including lymphopenia and hypoxia for influenza mortality. Immunopathology plays an important role in influenza pathogenesis. The disturbed homeostasis after virus infection consists of both an excessive inflammatory phase and an immune suppression phase, collectively described as viral sepsis. Multiple antiviral therapies have been tested and some were advanced to late-phase clinical trials, including polymerase inhibitors, hemagglutinin inhibitors, host-acting antivirals, monoclonal antibodies, and adjunctive immunomodulatory therapies. Combination therapies have been shown to increase antiviral efficacy and genetic resistance barrier. In this review, we summarized the recent advances in our understanding of the disease pathogenesis, as well as the progress in antiviral therapy development. We also pointed out current key knowledge gaps in influenza research. Hopefully, experience gained from seasonal influenza research will prepare us for the next influenza pandemic and emerging respiratory pathogens.

scholarly journals Extreme heterogeneity of influenza virus infection in single cells

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Alistair B Russell ◽  
Cole Trapnell ◽  
Jesse D Bloom
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Viral Infection ◽  
Single Cells ◽  
Influenza Virus Infection ◽  
Viral Gene ◽  
Viral Mrnas ◽  
Cellular Genes ◽  
Infected Cells ◽  
Cell Variation

Viral infection can dramatically alter a cell’s transcriptome. However, these changes have mostly been studied by bulk measurements on many cells. Here we use single-cell mRNA sequencing to examine the transcriptional consequences of influenza virus infection. We find extremely wide cell-to-cell variation in the productivity of viral transcription – viral transcripts comprise less than a percent of total mRNA in many infected cells, but a few cells derive over half their mRNA from virus. Some infected cells fail to express at least one viral gene, but this gene absence only partially explains variation in viral transcriptional load. Despite variation in viral load, the relative abundances of viral mRNAs are fairly consistent across infected cells. Activation of innate immune pathways is rare, but some cellular genes co-vary in abundance with the amount of viral mRNA. Overall, our results highlight the complexity of viral infection at the level of single cells.

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