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Biotechnology Advances 2023Shikimic acid (SA), a hydroaromatic natural product, is used as a chiral precursor for organic synthesis of oseltamivir (Tamiflu®, an antiviral drug). The process of... (Review)
Review
Shikimic acid (SA), a hydroaromatic natural product, is used as a chiral precursor for organic synthesis of oseltamivir (Tamiflu®, an antiviral drug). The process of microbial production of SA has recently undergone vigorous development. Particularly, the sustainable construction of recombinant Corynebacterium glutamicum (141.2 g/L) and Escherichia coli (87 g/L) laid a solid foundation for the microbial fermentation production of SA. However, its industrial application is restricted by limitations such as the lack of fermentation tests for industrial-scale and the requirement of growth-limiting factors, antibiotics, and inducers. Therefore, the development of SA biosensors and dynamic molecular switches, as well as genetic modification strategies and optimization of the fermentation process based on omics technology could improve the performance of SA-producing strains. In this review, recent advances in the development of SA-producing strains, including genetic modification strategies, metabolic pathway construction, and biosensor-assisted evolution, are discussed and critically reviewed. Finally, future challenges and perspectives for further reinforcing the development of robust SA-producing strains are predicted, providing theoretical guidance for the industrial production of SA.
Topics: Shikimic Acid; Escherichia coli; Oseltamivir; Antiviral Agents; Fermentation; Metabolic Engineering
PubMed: 36464143
DOI: 10.1016/j.biotechadv.2022.108073 -
Antiviral Research Dec 2016JNJ63623872 (formerly known as VX-787) is an inhibitor of influenza A virus polymerases through interaction with the viral PB2 subunit. This interaction blocks the... (Comparative Study)
Comparative Study
JNJ63623872 (formerly known as VX-787) is an inhibitor of influenza A virus polymerases through interaction with the viral PB2 subunit. This interaction blocks the cap-snatching activity of the virus that is essential for virus replication. Previously published work has documented antiviral activity of JNJ63623872 in cell culture and mouse infection studies. In this report, we extend the in vivo observations by comparing the efficacies of JNJ63623872 and oseltamivir in mice infected with influenza A/California/04/2009 (H1N1pdm) and A/Victoria/3/75 (H3N2) viruses. Animals received JNJ63623872 or oseltamivir orally twice daily for 10 days starting 2 h pre-infection. JNJ63623872 (2, 6, and 20 mg/kg/day) and oseltamivir (20 mg/kg/day) completely prevented death in the H1N1pdm virus infection. Weight loss at nadir was only 12% in mice receiving 2 mg/kg/day of JNJ63623872 compared to 23% and 32%, respectively, in oseltamivir-treated (20 mg/kg/day) and placebo groups. Lung hemorrhage scores, lung weights, and lung virus titers on day 6 were reduced in a dose-responsive manner by JNJ63623872 treatments, whereas oseltamivir treatments were not as effective. JNJ63623872 was less active against H3N2 virus infection, with more body weight loss occurring and only 30% survival at the 2-mg/kg/day dose. Lung scores, lung weights, and H3N2 viral titers in lungs of mice were reduced less by JNJ63623872 treatments compared to the H1N1pdm infection. Nevertheless, the 20-mg/kg/day dose of JNJ63623872 was more effective than oseltamivir (20 mg/kg/day) in improving body weight and reducing the severity of lung infection. JNJ63623872 appears to be an important new drug candidate to treat influenza A H1N1pdm and H3N2 virus infections.
Topics: Animals; Antiviral Agents; Drug Discovery; Drug Therapy, Combination; Indoles; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Lung; Mice; Orthomyxoviridae Infections; Oseltamivir; Pyridines; Pyrimidines; Pyrroles; Viral Load; Virus Replication
PubMed: 27771390
DOI: 10.1016/j.antiviral.2016.10.009 -
Annals of Family Medicine Mar 2018Studies examining the association between use of oseltamivir and neuropsychiatric events (including suicide) among children have had mixed findings and have been limited...
PURPOSE
Studies examining the association between use of oseltamivir and neuropsychiatric events (including suicide) among children have had mixed findings and have been limited by small sample size, reliance on older data, and potential confounding. We undertook an analysis that addresses these limitations.
METHODS
Using a national administrative claims database and a case-crossover design that minimized confounding, we analyzed data from 5 contemporary influenza seasons (2009-2013) for individuals aged 1 to 18 years and ascertained oseltamivir exposure from pharmacy dispensing.
RESULTS
We identified 21,407 suicide-related events during this study period, 251 of which were in oseltamivir-exposed children. In case-crossover analysis, we did not find any significant association with suicide either for oseltamivir exposure (odds ratio = 0.64; 95% CI, 0.39-1.00; = .05) or for influenza diagnosis alone (odds ratio = 0.63; 95% CI, 0.34-1.08; = .10).
CONCLUSION
Our findings suggest that oseltamivir does not increase risk of suicide in the pediatric population.
Topics: Adolescent; Antiviral Agents; Child; Child, Preschool; Cross-Over Studies; Databases, Factual; Female; Humans; Infant; Influenza, Human; Logistic Models; Male; Odds Ratio; Oseltamivir; Suicide; United States
PubMed: 29531106
DOI: 10.1370/afm.2183 -
Drug and Therapeutics Bulletin Mar 2024Hanula R, Bortolussi-Courval É, Mendel A, et al. Evaluation of oseltamivir used to prevent hospitalization in outpatients with influenza: a systematic review and... (Meta-Analysis)
Meta-Analysis
Hanula R, Bortolussi-Courval É, Mendel A, et al. Evaluation of oseltamivir used to prevent hospitalization in outpatients with influenza: a systematic review and meta-analysis. JAMA Internal Medicine 2024;184:18-27.
Topics: Humans; Oseltamivir; Influenza, Human; Antiviral Agents; Treatment Outcome; Hospitalization
PubMed: 38527768
DOI: 10.1136/dtb.2024.000016 -
MBio Aug 2023Obesity has been epidemiologically and empirically linked with more severe diseases upon influenza infection. To ameliorate severe disease, treatment with antivirals,...
Obesity has been epidemiologically and empirically linked with more severe diseases upon influenza infection. To ameliorate severe disease, treatment with antivirals, such as the neuraminidase inhibitor oseltamivir, is suggested to begin within days of infection especially in high-risk hosts. However, this treatment can be poorly effective and may generate resistance variants within the treated host. Here, we hypothesized that obesity would reduce oseltamivir treatment effectiveness in the genetically obese mouse model. We demonstrated that oseltamivir treatment does not improve viral clearance in obese mice. While no traditional variants associated with oseltamivir resistance emerged, we did note that drug treatment failed to quench the viral population and did lead to phenotypic drug resistance . Together, these studies suggest that the unique pathogenesis and immune responses in obese mice could have implications for pharmaceutical interventions and the within-host dynamics of the influenza virus population. IMPORTANCE Influenza virus infections, while typically resolving within days to weeks, can turn critical, especially in high-risk populations. Prompt antiviral administration is crucial to mitigating these severe sequalae, yet concerns remain if antiviral treatment is effective in hosts with obesity. Here, we show that oseltamivir does not improve viral clearance in genetically obese or type I interferon receptor-deficient mice. This suggests a blunted immune response may impair oseltamivir efficacy and render a host more susceptible to severe disease. This study furthers our understanding of oseltamivir treatment dynamics both systemically and in the lungs of obese mice, as well as the consequences of oseltamivir treatment for the within-host emergence of drug-resistant variants.
Topics: Mice; Animals; Humans; Oseltamivir; Mice, Obese; Influenza, Human; Influenza A Virus, H1N1 Subtype; Antiviral Agents; Neuraminidase; Drug Resistance, Viral
PubMed: 37341495
DOI: 10.1128/mbio.00887-23 -
Zhongguo Zhong Yao Za Zhi = Zhongguo... Aug 2022This study aims to obtain higher-level evidence by overviewing the Meta-analysis of Lianhua Qingwen preparations in the treatment of viral diseases including influenza,... (Review)
Review
This study aims to obtain higher-level evidence by overviewing the Meta-analysis of Lianhua Qingwen preparations in the treatment of viral diseases including influenza, coronavirus disease 2019(COVID-19), and hand, foot and mouth disease(HFMD). CNKI, Wanfang, VIP, China Clinical Trial Registry(ChiCTR), PubMed, EMbase, Web of Science, and Cochrane Library were searched for the Meta-analysis about the treatment of viral diseases with Lianhua Qingwen preparations from the database establishment to April 1, 2022. After literature screening and data extraction, AMSTAR2 and the grading of recommendations assessment, development and evaluations(GRADE) system were used to assess the methodological quality and evidence quality, respectively, and then the efficacy and safety outcomes of Lianhua Qingwen preparations in the treatment of viral diseases were summarized. Thirteen Meta-analysis were finally included, three of which were rated as low grade by AMSTAR2 and ten as very low grade. A total of 75 outcome indicators were obtained, involving influenza, COVID-19, and HFMD. According to the GRADE scoring results, the 75 outcome indicators included 5(6.7%) high-level indicators, 18(24.0%) mediate-level indicators, 25(33.3%) low-level evidence indicators, and 27(36.0%) very low-level indicators.(1)In the treatment of influenza, Lianhua Qingwen preparations exhibited better clinical efficacy than other Chinese patent medicines and Ribavirin and had similar clinical efficacy compared with Oseltamivir. Lianhua Qingwen preparations were superior to other Chinese patent medicines, Oseltamivir, and Ribavirin in alleviating clinical symptoms. They showed no significant differences from Oseltamivir or conventional anti-influenza treatment in terms of the time to and rate of negative result of viral nucleic acid test.(2)In the treatment of COVID-19, Lianhua Qingwen preparation alone or combined with conventional treatment was superior to conventional treatment in terms of total effective rate, main symptom subsidence rate and time, fever clearance rate, duration of fever, time to fever clearance, cough subsidence rate, time to cough subsidence, fatigue subsidence rate, time to fatigue subsidence, myalgia subsidence rate, expectoration subsidence rate, chest tightness subsidence rate, etc. Lianhua Qingwen preparations no difference from conventional treatment in terms of subsiding sore throat, nausea, diarrhea, loss of appetite, headache, and dyspnea. In terms of chest CT improvement rate, rate of progression to severe case, cure time, and hospitalization time, Lianhua Qingwen alone or in combination with conventional treatment was superior to conventional treatment.(3)In the treatment of HFMD, Lianhua Qingwen Granules was superior to conventional treatment in terms of total effective rate, average fever clearance time, time to herpes subsidence, and time to negative result of viral nucleic acid test.(4)In terms of safety, Lianhua Qingwen preparations led to low incidence of adverse reactions, all of which were mild and disappeared after drug withdrawal. The available evidence suggests that in the treatment of influenza, COVID-19, and HFMD, Lianhua Qingwen preparations can relieve the clinical symptoms, shorten the hospitalization time, and improve the chest CT. They have therapeutic effect and good safety in the treatment of viral diseases. However, due to the low quality of available studies, more high-quality clinical trials are needed to support the above conclusions.
Topics: Cough; Drugs, Chinese Herbal; Fatigue; Fever; Humans; Influenza, Human; Meta-Analysis as Topic; Nonprescription Drugs; Nucleic Acids; Oseltamivir; Ribavirin; COVID-19 Drug Treatment
PubMed: 36046880
DOI: 10.19540/j.cnki.cjcmm.20220510.501 -
Transplant Infectious Disease : An... Apr 2024Neuraminidase inhibitors, including oseltamivir, are the treatment standard for influenza. Baloxavir, a novel antiviral, demonstrated comparable outcomes to oseltamivir...
BACKGROUND
Neuraminidase inhibitors, including oseltamivir, are the treatment standard for influenza. Baloxavir, a novel antiviral, demonstrated comparable outcomes to oseltamivir in outpatients with influenza. Baloxavir was equally effective as oseltamivir in a retrospective study of hospitalized patients with influenza at our institution. However, the efficacy of baloxavir in immunocompromised patients is unclear.
METHODS
We conducted a retrospective cohort study of immunocompromised adult patients hospitalized with influenza A who received baloxavir from January 2019 to April 2019 or oseltamivir from January 2018 to April 2018. Demographic and clinical outcomes were assessed. Primary outcomes were time from antiviral initiation to resolution of hypoxia and fever. Secondary outcomes were length of stay (LOS), intensive care unit (ICU) care, ICU LOS, and 30-day mortality.
RESULTS
Of 95 total patients, 52 received baloxavir and 43 received oseltamivir. Other than younger age (57.5 vs. 65; p = .035) and longer duration between vaccination and symptom onset (114 vs. 86 days; p = .001) in the baloxavir group, baseline characteristics did not differ. H1 was the predominant subtype in the baloxavir group (65.3%) versus H3 in the oseltamivir group (85.7%). When comparing baloxavir to oseltamivir, there was no significant difference in median time from antiviral initiation to resolution of hypoxia (59.9 vs. 42.5 h) and to resolution of fever (21.6 vs. 26.6 h). There were no differences in secondary outcomes.
CONCLUSION
Baloxavir was not associated with longer time to resolution of hypoxia or fever in comparison to oseltamivir. Results must be taken in context of variations in seasonal influenza subtype and resistance rates.
Topics: Adult; Humans; Oseltamivir; Influenza, Human; Retrospective Studies; Oxazines; Pyridines; Thiepins; Antiviral Agents; Immunocompromised Host; Hypoxia; Dibenzothiepins; Morpholines; Pyridones; Triazines
PubMed: 38319665
DOI: 10.1111/tid.14249 -
Medicina (Kaunas, Lithuania) Aug 2023: Baloxavir marboxil is a novel cap-dependent endonuclease inhibitor prescribed for influenza treatment. Unlike neuraminidase inhibitors like oseltamivir, which impair...
: Baloxavir marboxil is a novel cap-dependent endonuclease inhibitor prescribed for influenza treatment. Unlike neuraminidase inhibitors like oseltamivir, which impair viral release from infected host cells, baloxavir blocks influenza virus proliferation by inhibiting viral mRNA transcription. This study aimed to compare the effectiveness of baloxavir and oseltamivir for the treatment of early childhood influenza. : Of 1410 patients diagnosed with influenza between 2015 and 2018 at a Japanese primary care outpatient clinic, 1111 pediatric patients aged 0-6 years who were treated with baloxavir ( = 555) or oseltamivir ( = 556) were enrolled retrospectively. The following clinical factors were compared between patients treated with baloxavir and oseltamivir: age, sex, time from fever onset to drug administration (<24 h or 24-48 h), time from drug administration to fever reduction, influenza type (A or B), and influenza vaccination before disease onset. The duration of the fever, which was used as an index of clinical effectiveness, was compared using the log-rank test. Clinical factors associated with fever duration were determined using multivariate logistic regression analysis. : Median age (3.0 vs. 2.5 years), influenza type A (99% vs. 47%), median duration from drug administration to fever resolution (1 day vs. 2 days), and influenza vaccination (done, 41% vs. not done, 65%) were significantly different between the baloxavir and oseltamivir groups ( < 0.001). The number of patients with a fever duration of one day was 553 (99.6%) in the baloxavir group and 6 (1.1%) in the oseltamivir group ( < 0.001). Baloxavir use was only significantly associated with fever duration in the multivariate analysis (odds ratio 50,201, < 0.001). Apparent adverse effects were not observed in the baloxavir-treated group. : Baloxavir treatment resulted in a shorter fever duration than oseltamivir treatment in early childhood influenza.
Topics: Child, Preschool; Humans; Child; Oseltamivir; Influenza, Human; Retrospective Studies; Dibenzothiepins; Fever
PubMed: 37763660
DOI: 10.3390/medicina59091543 -
PLoS Computational Biology Jul 2022Oseltamivir is a widely used influenza virus neuraminidase (NA) inhibitor that prevents the release of new virus particles from host cells. However,...
Oseltamivir is a widely used influenza virus neuraminidase (NA) inhibitor that prevents the release of new virus particles from host cells. However, oseltamivir-resistant strains have emerged, but effective drugs against them have not yet been developed. Elucidating the binding mechanisms between NA and oseltamivir may provide valuable information for the design of new drugs against NA mutants resistant to oseltamivir. Here, we conducted large-scale (353.4 μs) free-binding molecular dynamics simulations, together with a Markov State Model and an importance-sampling algorithm, to reveal the binding process of oseltamivir and NA. Ten metastable states and five major binding pathways were identified that validated and complemented previously discovered binding pathways, including the hypothesis that oseltamivir can be transferred from the secondary sialic acid binding site to the catalytic site. The discovery of multiple new metastable states, especially the stable bound state containing a water-mediated hydrogen bond between Arg118 and oseltamivir, may provide new insights into the improvement of NA inhibitors. We anticipated the findings presented here will facilitate the development of drugs capable of combating NA mutations.
Topics: Antiviral Agents; Drug Resistance, Viral; Enzyme Inhibitors; Humans; Influenza, Human; Neuraminidase; Oseltamivir
PubMed: 35901128
DOI: 10.1371/journal.pcbi.1010343 -
European Journal of Medicinal Chemistry Dec 2022Influenza with a tendency to cause pandemic and epidemic is an infectious disease with a high of morbidity and mortality. Neuraminidase (NA) inhibitors are proved to... (Review)
Review
Influenza with a tendency to cause pandemic and epidemic is an infectious disease with a high of morbidity and mortality. Neuraminidase (NA) inhibitors are proved to prevent and treat influenza. Among the four Neuraminidase inhibitors (NAIs) licensed, oseltamivir is most commonly used. With the extensive usage, several variants containing mutant NAs especially H274Y point mutation exhibit reduced susceptibility. In this review, we covered the current drugs available for influenza, the analysis of active site of NA, the mutant types of NAs and the molecular mechanism of drug resistance brought by H274Y mutant NAs. For recovering the susceptibility to oseltamivir, many series of oseltamivir analogues were designed. We present the details of the strategies of strengthening the interactions with S2 via introducing strong basic fragment, targeting additional subpockets and making full use of Zone X by modifying 3-pentyl of OC. PROTAC targeting NA and combination therapies are also introduced. Further, the advantages and disadvantages of these methods are also discussed.
Topics: Humans; Oseltamivir; Neuraminidase; Influenza, Human; Zanamivir; Mutation; Antiviral Agents; Enzyme Inhibitors; Guanidines; Glycoside Hydrolases; Drug Resistance, Viral
PubMed: 36055001
DOI: 10.1016/j.ejmech.2022.114711