scholarly journals Potent and Long-Acting Dimeric Inhibitors of Influenza Virus Neuraminidase Are Effective at a Once-Weekly Dosing Regimen

2004 ◽  
Vol 48 (12) ◽  
pp. 4542-4549 ◽  
Author(s):  
Simon J. F. Macdonald ◽  
Keith G. Watson ◽  
Rachel Cameron ◽  
David K. Chalmers ◽  
Derek A. Demaine ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Low Dose ◽  
Neuraminidase Inhibitor ◽  
Virus Infections ◽  
Dosing Regimen ◽  
Influenza Virus Replication ◽  
Long Acting ◽  
Influenza Virus Neuraminidase

ABSTRACT Dimeric derivatives (compounds 7 to 9) of the influenza virus neuraminidase inhibitor zanamivir (compound 2), which have linking groups of 14 to 18 atoms in length, are approximately 100-fold more potent inhibitors of influenza virus replication in vitro and in vivo than zanamivir. The observed optimum linker length of 18 to 22 Å, together with observations that the dimers cause aggregation of isolated neuraminidase tetramers and whole virus, indicate that the dimers benefit from multivalent binding via intertetramer and intervirion linkages. The outstanding long-lasting protective activities shown by compounds 8 and 9 in mouse influenza infectivity experiments and the extremely long residence times observed in the lungs of rats suggest that a single low dose of a dimer would provide effective treatment and prophylaxis for influenza virus infections.

scholarly journals Identification of GS 4104 as an Orally Bioavailable Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071

1998 ◽  
Vol 42 (3) ◽  
pp. 647-653 ◽  
Author(s):  
Weixing Li ◽  
Paul A. Escarpe ◽  
Eugene J. Eisenberg ◽  
Kenneth C. Cundy ◽  
Clive Sweet ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Ethyl Ester ◽  
Oral Bioavailability ◽  
Influenza A ◽  
Neuraminidase Inhibitor ◽  
Virus Infections ◽  
Neuraminidase Activity ◽  
Orally Bioavailable ◽  
Influenza Virus Neuraminidase

ABSTRACT GS 4071 is a potent carbocyclic transition-state analog inhibitor of influenza virus neuraminidase with activity against both influenza A and B viruses in vitro. GS 4116, the guanidino analog of GS 4071, is a 10-fold more potent inhibitor of influenza virus replication in tissue culture than GS 4071. In this study we determined the oral bioavailabilities of GS 4071, GS 4116, and their respective ethyl ester prodrugs in rats. Both parent compounds and the prodrug of the guanidino analog exhibited poor oral bioavailability (2 to 4%) and low peak concentrations in plasma (C maxs; C max<0.06 μg/ml). In contrast, GS 4104, the ethyl ester prodrug of GS 4071, exhibited good oral bioavailability (35%) as GS 4071 and high C maxs of GS 4071 (Cmax = 0.47 μg/ml) which are 150 times the concentration necessary to inhibit influenza virus neuraminidase activity by 90%. The bioavailability of GS 4104 as GS 4071 was also determined in mice (30%), ferrets (11%), and dogs (73%). The plasma of all four species exhibited high, sustained concentrations of GS 4071 such that at 12 h postdosing the concentrations of GS 4071 in plasma exceeded those necessary to inhibit influenza virus neuraminidase activity by 90%. These results demonstrate that GS 4104 is an orally bioavailable prodrug of GS 4071 in animals and that it has the potential to be an oral agent for the prevention and treatment of influenza A and B virus infections in humans.

scholarly journals In Vitro and In Vivo Activities of Anti-Influenza Virus Compound T-705

2002 ◽  
Vol 46 (4) ◽  
pp. 977-981 ◽  
Author(s):  
Y. Furuta ◽  
K. Takahashi ◽  
Y. Fukuda ◽  
M. Kuno ◽  
T. Kamiyama ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Inhibitory Activity ◽  
Influenza A ◽  
Rna Viruses ◽  
Neuraminidase Inhibitor ◽  
Virus Infections ◽  
Dna Viruses ◽  
Virus Rna

ABSTRACT T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has been found to have potent and selective inhibitory activity against influenza virus. In an in vitro plaque reduction assay, T-705 showed potent inhibitory activity against influenza A, B, and C viruses, with 50% inhibitory concentrations (IC50s) of 0.013 to 0.48 μg/ml, while it showed no cytotoxicity at concentrations up to 1,000 μg/ml in Madin-Darby canine kidney cells. The selectivity index for influenza virus was more than 2,000. It was also active against a neuraminidase inhibitor-resistant virus and some amantadine-resistant viruses. T-705 showed weak activity against non-influenza virus RNA viruses, with the IC50s being higher for non-influenza virus RNA viruses than for influenza virus, and it had no activity against DNA viruses. Orally administered T-705 at 100 mg/kg of body weight/day (four times a day) for 5 days significantly reduced the mean pulmonary virus yields and the rate of mortality in mice infected with influenza virus A/PR/8/34 (3 × 102 PFU). These results suggest that T-705 may be a compound that is useful and highly selective against influenza virus infections and that has a mode of action different from those of commercially available drugs, such as amantadine, rimantadine, and neuraminidase inhibitors.

scholarly journals Natural and directed antigenic drift of the H1 influenza virus hemagglutinin stalk domain

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Christopher S. Anderson ◽  
Sandra Ortega ◽  
Francisco A. Chaves ◽  
Amelia M. Clark ◽  
Hongmei Yang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Viral Fitness ◽  
Antigenic Drift ◽  
Virus Infections ◽  
Head Region ◽  
Immune Pressure ◽  
Stalk Domain ◽  
Ha Protein

Abstract The induction of antibodies specific for the influenza HA protein stalk domain is being pursued as a universal strategy against influenza virus infections. However, little work has been done looking at natural or induced antigenic variability in this domain and the effects on viral fitness. We analyzed human H1 HA head and stalk domain sequences and found substantial variability in both, although variability was highest in the head region. Furthermore, using human immune sera from pandemic A/California/04/2009 immune subjects and mAbs specific for the stalk domain, viruses were selected in vitro containing mutations in both domains that partially contributed to immune evasion. Recombinant viruses encoding amino acid changes in the HA stalk domain replicated well in vitro, and viruses incorporating two of the stalk mutations retained pathogenicity in vivo. These findings demonstrate that the HA protein stalk domain can undergo limited drift under immune pressure and the viruses can retain fitness and virulence in vivo, findings which are important to consider in the context of vaccination targeting this domain.

scholarly journals Role of Initiating Nucleoside Triphosphate Concentrations in the Regulation of Influenza Virus Replication and Transcription

2008 ◽  
Vol 82 (14) ◽  
pp. 6902-6910 ◽  
Author(s):  
Frank T. Vreede ◽  
Hugh Gifford ◽  
George G. Brownlee
Keyword(s):  
Influenza Virus ◽  
Virus Replication ◽  
Influenza A ◽  
De Novo ◽  
Nucleoside Triphosphate ◽  
Ribonucleoprotein Complexes ◽  
Influenza Virus Replication ◽  
High Concentrations

ABSTRACT The mechanisms regulating the synthesis of mRNA, cRNA, and viral genomic RNA (vRNA) by the influenza A virus RNA-dependent RNA polymerase are not fully understood. Previous studies in our laboratory have shown that virion-derived viral ribonucleoprotein complexes synthesize both mRNA and cRNA in vitro and early in the infection cycle in vivo. Our continued studies showed that de novo synthesis of cRNA in vitro is more sensitive to the concentrations of ATP, CTP, and GTP than capped-primer-dependent synthesis of mRNA. Using rescued recombinant influenza A/WSN/33 viruses, we now demonstrate that the 3′-terminal sequence of the vRNA promoter dictates the requirement for a high nucleoside triphosphate (NTP) concentration during de novo-initiated replication to cRNA, whereas this is not the case for the extension of capped primers during transcription to mRNA. In contrast to some other viral polymerases, for which only the initiating NTP is required at high concentrations, influenza virus polymerase requires high concentrations of the first three NTPs. In addition, we show that base pair mutations in the vRNA promoter can lead to nontemplated dead-end mutations during replication to cRNA in vivo. Based on our observations, we propose a new model for the de novo initiation of influenza virus replication.

scholarly journals Gentamicin Induced Microbiome Adaptations Associate With Increased BCAA Levels and Enhance Severity of Influenza Infection

2021 ◽  
Vol 11 ◽  
Author(s):  
Yakun Sun ◽  
Zhili He ◽  
Jiajia Li ◽  
Saisai Gong ◽  
Shunzong Yuan ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Gut Microbiota ◽  
Influenza Infection ◽  
Alpha Diversity ◽  
Virus Infections ◽  
Bone Marrow Derived Cells ◽  
Branched Chain ◽  
Lung Immunity

Involvement of gut microbiota in pulmonary disease by the gut-lung axis has been widely observed. However, the cross-talk messengers between respiratory mucosal immunity and gut microbiota are largely unknown. Using selective pharmacologic destruction of gut microenvironment mouse models, we found gut microbiota displayed significantly lower alpha diversity and relative abundance of bacteria in Gentamicin treated mice. Metagenomic studies revealed functional differences in gut bacteria in altering metabolic profiles in mice blood. Branched-chain amino acids (BCAAs) are the essential factors linked between gut and lung. During this process, selective destruction of gut microbiota by Gentamicin induced high levels of BCAAs, and the high levels of BCAAs impacted the lung immunity against influenza virus. In vivo, Gentamicin-treated mice or mice fed with high BCAAs diets displayed reduced survival. At the sites of infection, the number of CD11b+Ly6G+ cells decreased, and CD8+ T cells increased accompanied by exuberant expression of pro-inflammatory cytokines could result in tissue damage. CD11b+Ly6G+ cells transplantation conferred remarkable protection from influenza virus infections. In vitro, BCAAs promoted bone marrow-derived cells differentiation to dendritic cells. Taken together, these findings demonstrate that Gentamicin induced disruption of the gut microbiota leads to increased BCAA levels that suppress CD11b+Ly6c+ cell development in association with overactive CD8+ T responses which may contribute to enhanced severity of the viral infection.

scholarly journals Cryptoporus volvatus Extract Inhibits Influenza Virus Replication In Vitro and In Vivo

PLoS ONE ◽  
2014 ◽  
Vol 9 (12) ◽  
pp. e113604 ◽  
Author(s):  
Li Gao ◽  
Yipeng Sun ◽  
Jianyong Si ◽  
Jinhua Liu ◽  
Guibo Sun ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Replication ◽  
Influenza Virus Replication

scholarly journals Ethanol Extract of Caesalpinia decapetala Inhibits Influenza Virus Infection In Vitro and In Vivo

Viruses ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 557 ◽  
Author(s):  
Li Zhang ◽  
Jungang Chen ◽  
Chang Ke ◽  
Haiwei Zhang ◽  
Shoujun Zhang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Antiviral Agents ◽  
Influenza Virus Infection ◽  
Virus Titer ◽  
Ethanol Extract ◽  
Influenza Viruses ◽  
Virus Infections

Influenza virus infections can lead to viral pneumonia and acute respiratory distress syndrome in severe cases, causing significant morbidity and mortality and posing a great threat to human health. Because of the diversity of influenza virus strains and drug resistance to the current direct antiviral agents, there have been no effective drugs as yet to cure all patients infected by influenza viruses. Natural products from plants contain compounds with diverse structures that have the potential to interact with multiple host and virus factors. In this study, we identified the ethanol extract of Caesalpinia decapetala (Roth) Alston (EEC) as an inhibitor against the replication of a panel of influenza A and B viruses both on human pulmonary epithelial A549 and human monocytic U937 cells. The animal study revealed that EEC administration reduces the weight loss and improves the survival rate of mice infected with lethal influenza virus. Also, EEC treatment attenuated lung injury and reduced virus titer significantly. In conclusion, we showed that EEC has antiviral activity both in vitro and in vivo, suggesting that the plant C. decapetala has the potential to be further developed as a resource of new anti-influenza drugs.

Inhibition of influenza virus infections in mice by GS4104, an orally effective influenza virus neuraminidase inhibitor

1998 ◽  
Vol 37 (2) ◽  
pp. 107-120 ◽  
Author(s):  
Robert W. Sidwell ◽  
John H. Huffman ◽  
Dale L. Barnard ◽  
Kevin W. Bailey ◽  
Min-Hui Wong ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Neuraminidase Inhibitor ◽  
Virus Infections ◽  
Influenza Virus Neuraminidase

scholarly journals Novel epitopes of human monoclonal antibodies targeting the influenza virus N1 neuraminidase

2021 ◽  
Author(s):  
Ericka Kirkpatrick Roubidoux ◽  
Meagan McMahon ◽  
Juan Manuel Carreno ◽  
Christina Capuano ◽  
Kaijun Jiang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Monoclonal Antibodies ◽  
Serial Passage ◽  
Viral Fitness ◽  
Escape Mutant ◽  
Human Antibody ◽  
Human Monoclonal Antibodies ◽  
Influenza Virus Neuraminidase

Influenza virus neuraminidase (NA) targeting antibodies are an independent correlate of protection against infection. Antibodies against the NA act by blocking enzymatic activity, preventing virus release and transmission. As we advance the development of improved influenza virus vaccines that incorporate standard amounts of NA antigen, it is important to identify the antigenic targets of human monoclonal antibodies (mAbs). Additionally, it is important to understand how escape from mAbs changes viral fitness. Here, we describe escape mutants generated by serial passage of A/Netherlands/602/2009 (H1N1) in the presence of human anti-N1 mAbs. We observed escape mutations on the N1 protein around the enzymatic site (S364N, N369T and R430Q) and also detected escape mutations located on the sides and bottom of the NA (N88D, N270D and Q313K/R). We found that a majority of escape mutant viruses had increased fitness in vitro but not in vivo. This work increases our understanding of how human antibody responses target the N1 protein.

Sign in / Sign up

Export Citation Format

Share Document