scholarly journals Laninamivir Prodrug CS-8958, a Long-Acting Neuraminidase Inhibitor, Shows Superior Anti-Influenza Virus Activity after a Single Administration

2010 ◽  
Vol 54 (3) ◽  
pp. 1256-1264 ◽  
Author(s):  
Shuku Kubo ◽  
Takanori Tomozawa ◽  
Masayo Kakuta ◽  
Akane Tokumitsu ◽  
Makoto Yamashita
Keyword(s):  
Influenza Virus ◽  
Influenza Virus Infection ◽  
Neuraminidase Inhibitor ◽  
Infection Model ◽  
Single Administration ◽  
Mouse Infection Model ◽  
Significant Efficacy ◽  
Long Acting ◽  
Oseltamivir Phosphate

ABSTRACT Two neuraminidase (NA) inhibitors, zanamivir (Relenza) and oseltamivir phosphate (Tamiflu), have been licensed for use for the treatment and prophylaxis of influenza. We have reported on laninamivir (code name, R-125489), a novel neuraminidase inhibitor, and have discovered that the laninamivir prodrug CS-8958 worked as a long-acting neuraminidase inhibitor in a mouse influenza virus infection model when it is intranasally administered. In this study, CS-8958 was administered just once 7 days before infection and showed significant efficacy in vivo. The efficacy of a single administration of CS-8958 after viral infection was then compared with that of repeated administrations of oseltamivir phosphate or zanamivir in mice and ferrets. CS-8958 showed efficacy superior or similar to the efficacies of the two licensed NA inhibitors. CS-8958 also significantly reduced the titers of an oseltamivir-resistant H1N1 virus with a neuraminidase H274Y substitution in a mouse infection model. These results suggest that since CS-8958 is characteristically long lasting in the lungs, it may be ideal for the prophylaxis and treatment of influenza.

scholarly journals CS-8958, a Prodrug of the New Neuraminidase Inhibitor R-125489, Shows Long-Acting Anti-Influenza Virus Activity

2008 ◽  
Vol 53 (1) ◽  
pp. 186-192 ◽  
Author(s):  
Makoto Yamashita ◽  
Takanori Tomozawa ◽  
Masayo Kakuta ◽  
Akane Tokumitsu ◽  
Hatsumi Nasu ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Acyl Chain ◽  
Neuraminidase Inhibitor ◽  
Influenza Viruses ◽  
Infection Model ◽  
Acyl Chain Length ◽  
Long Acting ◽  
Survival Effect ◽  
First Time

ABSTRACT Two neuraminidase (NA) inhibitors, zanamivir (Relenza) and oseltamivir phosphate (Tamiflu), have been licensed for the treatment of and prophylaxis against influenza. In this paper, the new potent NA inhibitor R-125489 is reported for the first time. R-125489 inhibited the NA activities of various type A and B influenza viruses, including subtypes N1 to N9 and oseltamivir-resistant viruses. The survival effect of R-125489 was shown to be similar to that of zanamivir when administered intranasally in a mouse influenza virus A/Puerto Rico/8/34 infection model. Moreover, we found that the esterified form of R-125489 showed improved efficacy compared to R-125489 and zanamivir, depending on the acyl chain length, and that 3-(O)-octanoyl R-125489 (CS-8958) was the best compound in terms of its life-prolonging effect (P < 0.0001, compared to zanamivir) in the same infection model. A prolonged survival effect was observed after a single administration of CS-8958, even if it was given 7 days before infection. It is suggested that intranasally administered CS-8958 works as a long-acting NA inhibitor and shows in vivo efficacy as a result of a single intranasal administration.

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 CS-8958, a Prodrug of the Novel Neuraminidase Inhibitor R-125489, Demonstrates a Favorable Long-Retention Profile in the Mouse Respiratory Tract

2009 ◽  
Vol 53 (11) ◽  
pp. 4845-4851 ◽  
Author(s):  
Kumiko Koyama ◽  
Makoto Takahashi ◽  
Masataka Oitate ◽  
Naoko Nakai ◽  
Hideo Takakusa ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Active Form ◽  
Neuraminidase Inhibitor ◽  
The Novel ◽  
Esterase Inhibitors ◽  
Elimination Half ◽  
Significant Efficacy ◽  
Long Acting ◽  
Pharmacologically Active

ABSTRACT CS-8958 is a prodrug of the pharmacologically active form R-125489, a selective neuraminidase inhibitor, and has long-acting anti-influenza virus activity in vivo. In this study, the tissue distribution profiles after a single intranasal administration of CS-8958 (0.5 μmol/kg of body weight) to mice were investigated, focusing especially on the retention of CS-8958 in the respiratory tract by comparing it with R-125489 and a marketed drug, zanamivir. After administration of [14C]CS-8958, radioactivity was retained in the respiratory tract over long periods. At 24 h postdose, the radioactivity concentrations after administration of [14C]CS-8958 were approximately 10-fold higher in both the trachea and the lung than those of [14C]R-125489 and [14C]zanamivir. The [14C]CS-8958-derived radioactivity present in these two tissues consisted both of unchanged CS-8958 and of R-125489 at 1 h postdose, while only R-125489, and no other metabolites, was detected at 24 h postdose. After administration of unlabeled CS-8958, CS-8958 was rapidly eliminated from the lungs, whereas the lung R-125489 concentration reached a maximum at 3 h postdose and gradually declined, with an elimination half-life of 41.4 h. The conversion of CS-8958 to R-125489 was observed in mouse trachea and lung S9 fractions and was inhibited by esterase inhibitors, such as diisopropylfluorophosphate and bis-p-nitrophenylphosphate. These results demonstrated that CS-8958 administered intranasally to mice was efficiently converted to R-125489 by a hydrolase(s) such as carboxylesterase, and then R-125489 was slowly eliminated from the respiratory tract. These data support the finding that CS-8958 has potential as a long-acting neuraminidase inhibitor, leading to significant efficacy as an anti-influenza drug by a single treatment.

scholarly journals Intrapulmonary Distribution and Pharmacokinetics of Laninamivir, a Neuraminidase Inhibitor, after a Single Inhaled Administration of Its Prodrug, Laninamivir Octanoate, in Healthy Volunteers

2012 ◽  
Vol 56 (7) ◽  
pp. 3873-3878 ◽  
Author(s):  
Hitoshi Ishizuka ◽  
Kaoru Toyama ◽  
Satoshi Yoshiba ◽  
Hiromi Okabe ◽  
Hidetoshi Furuie
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza Virus Infection ◽  
Drug Distribution ◽  
Neuraminidase Inhibitor ◽  
Open Label ◽  
Liquid Chromatography Tandem Mass ◽  
Long Acting ◽  
Pharmacologically Active ◽  
Adult Volunteers

ABSTRACTA single inhaled dose of laninamivir octanoate (LO), a long-acting neuraminidase inhibitor, exhibits efficacy in treating both adult and pediatric patients with influenza virus infection. The intrapulmonary pharmacokinetics (PK) of LO and laninamivir, a pharmacologically active metabolite, were investigated by a single-center, open-label study of healthy adult volunteers. Subgroups of five subjects each underwent bronchoalveolar lavage (BAL) 4, 8, 24, 48, 72, 168, and 240 h following a single inhaled administration of LO (40 mg). Plasma, BAL fluid, and alveolar macrophages (AM) were analyzed to determine LO and laninamivir concentrations, using validated liquid chromatography-tandem mass spectrometry methods. The concentrations in epithelial lining fluid (ELF) and AM from the first and subsequent BAL fluid samples were determined separately to explore the drug distribution in airways. Mean laninamivir concentrations in ELF, calculated using the first BAL fluids and BAL fluids collected 4 h after inhaled administration, were 8.57 and 2.40 μg/ml, respectively. The laninamivir concentration in ELF decreased with a longer half-life than that in plasma, and it exceeded the 50% inhibitory concentrations for viral neuraminidases at all time points examined for 240 h after the inhalation. Laninamivir exposure in ELF from the first BAL samples was 3.2 times higher than that in ELF from the subsequent BAL fluid samples. ELF concentration profiles of laninamivir support its long-lasting effect for treatment of patients with influenza virus infection by a single inhaled administration.

scholarly journals The zinc transporter ZnuABC is critical for the virulence of Chromobacterium violaceum and contributes to diverse zinc-dependent physiological processes

2021 ◽  
Author(s):  
Renato E. R. S. Santos ◽  
Waldir P. da Silva Júnior ◽  
Simone A. Harrison ◽  
Eric P Skaar ◽  
Walter J. Chazin ◽  
...  
Keyword(s):  
Mutant Strain ◽  
Zinc Uptake ◽  
Chromobacterium Violaceum ◽  
Host Protein ◽  
Infection Model ◽  
Uptake System ◽  
Environmental Bacterium ◽  
Mouse Infection Model ◽  
Synthetic Metal

Chromobacterium violaceum is a ubiquitous environmental bacterium that causes sporadic life-threatening infections in humans. How C. violaceum acquires zinc to colonize environmental and host niches is unknown. In this work, we demonstrated that C. violaceum employs the zinc uptake system ZnuABC to overcome zinc limitation in the host, ensuring the zinc supply for several physiological demands. Our data indicated that the C. violaceum ZnuABC transporter is encoded in a zur-CV_RS15045-CV_RS15040-znuCBA operon. This operon was repressed by the zinc uptake regulator Zur and derepressed in the presence of the host protein calprotectin (CP) and the synthetic metal chelator EDTA. A ΔznuCBA mutant strain showed impaired growth under these zinc-chelated conditions. Moreover, the deletion of znuCBA provoked a reduction in violacein production, swimming motility, biofilm formation, and bacterial competition. Remarkably, the ΔznuCBA mutant strain was highly attenuated for virulence in an in vivo mouse infection model and showed a low capacity to colonize the liver, grow in the presence of CP, and resist neutrophil killing. Overall, our findings demonstrate that ZnuABC is essential for C. violaceum virulence, contributing to subvert the zinc-based host nutritional immunity.

scholarly journals Nasal commensal, Staphylococcus epidermidis shapes the mucosal environment to prevent influenza virus invasion through Serpine1 induction

2020 ◽  
Author(s):  
Ara Jo ◽  
Jina Won ◽  
Chan Hee Chil ◽  
Jae Young Choi ◽  
Kang-Mu Lee ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Respiratory Tract ◽  
Protease Inhibitor ◽  
Serine Protease ◽  
Nasal Mucosa ◽  
Staphylococcus Epidermidis ◽  
Influenza Virus Infection ◽  
Serine Protease Inhibitor ◽  
Cellular Environment

ABSTRACTOur recent study presented evidence that Staphylococcus epidermidis (S. epidermidis) was the most frequently encountered microbiome component in healthy human nasal mucus and that S. epidermidis could induce interferon (IFN)-dependent innate immunity to control acute viral lung infection. The serine protease inhibitor Serpine1 was identified to inhibit influenza A virus (IAV) spread by inhibiting glycoprotein cleavage, and the current study supports an additional mechanism of Serpine1 induction in the nasal mucosa, which can be regulated through S. epidermidis and IFN signaling. The exposure of in vivo mice to human S. epidermidis increased IFN-λ secretion in nasal mucosa and prevented an increase in the burden of IAV in the lung. S. epidermidis-inoculated mice exhibited the significant induction of Serpine1 in vivo in the nasal mucosa, and by targeting airway protease, S. epidermidis-induced Serpine1 inhibited the intracellular invasion of IAV to the nasal epithelium and led to restriction of IAV spreading to the lung. Furthermore, IFN-λ secretion was involved in the regulation of Serpine1 in S. epidermidis-inoculated nasal epithelial cells and in vivo nasal mucosa, and this was biologically relevant for the role of Serpine1 as an interferon-stimulated gene in the upper airway. Together, our findings reveal that human nasal commensal S. epidermidis manipulates the suppression of serine protease in in vivo nasal mucosa through Serpine1 induction and protects the nasal mucosa from IAV invasion through IFN-λ signaling.IMPORTANCEPreviously, we proved that nasal microbiome could enhance IFN-related innate immune responses to protect the respiratory tract against influenza virus infection. The present study shows a great understanding of the intimate association of S. epidermidis-regulated IFN-lambda induction and serine protease inhibitor in nasal mucosa. Our data demonstrate that S. epidermidis-regulated Serpine1 suppresses the invasion of influenza virus through suppression of airway serine protease at the level of nasal mucosa and impedes IAV spread to the respiratory tract. Thus, human nasal commensal S. epidermidis represents a therapeutic potential for treating respiratory viral infections via the change of cellular environment in respiratory tract.

scholarly journals Linear polysialoside outperforms dendritic analogs for inhibition of influenza virus infection in vitro and in vivo

Biomaterials ◽  
2017 ◽  
Vol 138 ◽  
pp. 22-34 ◽  
Author(s):  
Sumati Bhatia ◽  
Daniel Lauster ◽  
Markus Bardua ◽  
Kai Ludwig ◽  
Stefano Angioletti-Uberti ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza Virus Infection

scholarly journals Directed Evolution of an Influenza Reporter Virus To Restore Replication and Virulence and Enhance Noninvasive Bioluminescence Imaging in Mice

2018 ◽  
Vol 92 (16) ◽  
Author(s):  
Hui Cai ◽  
Meisui Liu ◽  
Charles J. Russell
Keyword(s):  
Gene Expression ◽  
Influenza Virus ◽  
Virus Infection ◽  
Directed Evolution ◽  
Influenza Virus Infection ◽  
Foreign Gene ◽  
Reporter Virus ◽  
Wild Type ◽  
Bioluminescence Signal

ABSTRACTReporter viruses provide a powerful tool to study infection, yet incorporating a nonessential gene often results in virus attenuation and genetic instability. Here, we used directed evolution of a luciferase-expressing pandemic H1N1 (pH1N1) 2009 influenza A virus in mice to restore replication kinetics and virulence, increase the bioluminescence signal, and maintain reporter gene expression. An unadapted pH1N1 virus withNanoLuc luciferaseinserted into the 5′ end of the PA gene segment grew to titers 10-fold less than those of the wild type in MDCK cells and in DBA/2 mice and was less virulent. For 12 rounds, we propagated DBA/2 lung samples with the highest bioluminescence-to-titer ratios. Every three rounds, we comparedin vivoreplication, weight loss, mortality, and bioluminescence. Mouse-adapted virus after 9 rounds (MA-9) had the highest relative bioluminescence signal and had wild-type-like fitness and virulence in DBA/2 mice. Using reverse genetics, we discovered fitness was restored in virus rPB2-MA9/PA-D479N by a combination of PA-D479N and PB2-E158G amino acid mutations andPB2noncoding mutations C1161T and C1977T. rPB2-MA9/PA-D479N has increased mRNA transcription, which helps restore wild-type-like phenotypes in DBA/2 and BALB/c mice. Overall, the results demonstrate that directed evolution that maximizes foreign-gene expression while maintaining genetic stability is an effective method to restore wild-type-likein vivofitness of a reporter virus. Virus rPB2-MA9/PA-D479N is expected to be a useful tool for noninvasive imaging of pH1N1 influenza virus infection and clearance while analyzing virus-host interactions and developing new therapeutics and vaccines.IMPORTANCEInfluenza viruses contribute to 290,000 to 650,000 deaths globally each year. Infection is studied in mice to learn how the virus causes sickness and to develop new drugs and vaccines. During experiments, scientists have needed to euthanize groups of mice at different times to measure the amount of infectious virus in mouse tissues. By inserting a foreign gene that causes infected cells to light up, scientists could see infection spread in living mice. Unfortunately, adding an extra gene not needed by the virus slowed it down and made it weaker. Here, we used a new strategy to restore the fitness and lethality of an influenza reporter virus; we adapted it to mouse lungs and selected for variants that had the greatest light signal. The adapted virus can be used to study influenza virus infection, immunology, and disease in living mice. The strategy can also be used to adapt other viruses.

scholarly journals Methionyl-tRNA synthetase inhibitor has potent in vivo activity in a novel Giardia lamblia luciferase murine infection model

2020 ◽  
Vol 75 (5) ◽  
pp. 1218-1227
Author(s):  
Samantha A Michaels ◽  
Han-Wei Shih ◽  
Bailin Zhang ◽  
Edelmar D Navaluna ◽  
Zhongsheng Zhang ◽  
...  
Keyword(s):  
Giardia Lamblia ◽  
Trna Synthetase ◽  
Luciferase Reporter ◽  
Infection Model ◽  
Cell Assay ◽  
Mouse Infection Model ◽  
Mouse Infection ◽  
Methionyl Trna Synthetase

Abstract Background Methionyl-tRNA synthetase (MetRS) inhibitors are under investigation for the treatment of intestinal infections caused by Giardia lamblia. Objectives To properly analyse the therapeutic potential of the MetRS inhibitor 1717, experimental tools including a robust cell-based assay and a murine model of infection were developed based on novel strains of G. lamblia that employ luciferase reporter systems to quantify viable parasites. Methods Systematic screening of Giardia-specific promoters and luciferase variants led to the development of a strain expressing the click beetle green luciferase. Further modifying this strain to express NanoLuc created a dual reporter strain capable of quantifying parasites in both the trophozoite and cyst stages. These strains were used to develop a high-throughput cell assay and a mouse infection model. A library of MetRS inhibitors was screened in the cell assay and Compound-1717 was tested for efficacy in the mouse infection model. Results Cell viability in in vitro compound screens was quantified via bioluminescence readouts while infection loads in mice were monitored with non-invasive whole-animal imaging and faecal analysis. Compound-1717 was effective in clearing mice of Giardia infection in 3 days at varying doses, which was supported by data from enzymatic and phenotypic cell assays. Conclusions The new in vitro and in vivo assays based on luciferase expression by engineered G. lamblia strains are useful for the discovery and development of new therapeutics for giardiasis. MetRS inhibitors, as validated by Compound-1717, have promising anti-giardiasis properties that merit further study as alternative therapeutics.

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