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MBio May 2024Influenza viruses (IVs) threaten global human health due to the high morbidity, infection, and mortality rates. Currently, the influenza drugs recommended by the Food...
Influenza viruses (IVs) threaten global human health due to the high morbidity, infection, and mortality rates. Currently, the influenza drugs recommended by the Food and Drug Administration are oseltamivir, zanamivir, peramivir, and baloxavir marboxil. These recommended antivirals are currently effective for major subtypes of IVs as the compounds target conserved domains in neuraminidase or polymerase acidic (PA) protein. However, this trend may gradually change due to the selection of antiviral drugs and the natural evolution of IVs. Therefore, there is an urgent need to develop drugs related to the treatment of influenza to deal with the next pandemic. Here, we summarized the cutting-edge research in mechanism of action, inhibitory activity, and clinical efficacy of drugs that have been approved and drugs that are still in clinical trials for influenza treatment. We hope this review will provide up-to-date and comprehensive information on influenza antivirals and generate hypotheses for screens and development of new broad-spectrum influenza drugs in the near future.
Topics: Humans; Antiviral Agents; Clinical Trials as Topic; Dibenzothiepins; Drug Development; Influenza, Human; Morpholines; Orthomyxoviridae; Pyridones; Triazines; Zanamivir
PubMed: 38551343
DOI: 10.1128/mbio.00175-24 -
Viruses Mar 2024The H274Y substitution (N2 numbering) in neuraminidase (NA) N1 confers oseltamivir resistance to A(H1N1) influenza viruses. This resistance has been associated with...
The H274Y substitution (N2 numbering) in neuraminidase (NA) N1 confers oseltamivir resistance to A(H1N1) influenza viruses. This resistance has been associated with reduced N1 expression using transfected cells, but the effect of this substitution on the enzymatic properties and on the expression of other group-1-NA subtypes is unknown. The aim of the present study was to evaluate the antiviral resistance, enzymatic properties, and expression of wild-type (WT) and H274Y-substituted NA for each group-1-NA. To this end, viruses with WT or H274Y-substituted NA (N1pdm09 or avian N4, N5 or N8) were generated by reverse genetics, and for each reverse-genetic virus, antiviral susceptibility, NA affinity (Km), and maximum velocity (Vm) were measured. The enzymatic properties were coupled with NA quantification on concentrated reverse genetic viruses using mass spectrometry. The H274Y-NA substitution resulted in highly reduced inhibition by oseltamivir and normal inhibition by zanamivir and laninamivir. This resistance was associated with a reduced affinity for MUNANA substrate and a conserved Vm in all viruses. NA quantification was not significantly different between viruses carrying WT or H274Y-N1, N4 or N8, but was lower for viruses carrying H274Y-N5 compared to those carrying a WT-N5. In conclusion, the H274Y-NA substitution of different group-1-NAs systematically reduced their affinity for MUNANA substrate without a significant impact on NA Vm. The impact of the H274Y-NA substitution on viral NA expression was different according to the studied NA.
Topics: Humans; Oseltamivir; Antiviral Agents; Influenza A virus; Neuraminidase; Influenza A Virus, H1N1 Subtype; Reverse Genetics; Drug Resistance, Viral; Influenza, Human; Amino Acid Substitution; Enzyme Inhibitors
PubMed: 38543754
DOI: 10.3390/v16030388 -
The Pediatric Infectious Disease Journal Jul 2024The objective of this study was to investigate the clinical and laboratory features of acute benign myositis associated with influenza A virus infection in children.
OBJECTIVE
The objective of this study was to investigate the clinical and laboratory features of acute benign myositis associated with influenza A virus infection in children.
METHODS
A retrospective analysis was performed on the clinical data of 118 children with acute benign myositis associated with influenza A virus infection who were admitted to the Children's Hospital of Chongqing Medical University during the epidemic period of influenza A from February 2023 to May 2023.
RESULTS
(1) Most of the 118 children were preschool- or school-age. The most common symptom was sudden lower limb pain after fever, and bilateral calf myalgia was more common. The muscle enzyme spectrum ranged from 187.21 to 32191.00 μg/L (median: 3053 μg/L). Creatine kinase isoenzymes ranged from 5.15 to 749.7 μg/L (median 41.82 μg/L). Myoglobin ranged from 102.79 to 1200 μg/L (median 674.9 μg/L). (3) Examination: electromyography, muscle color Doppler ultrasound, radiograph and cardiac color Doppler ultrasound in Benign acute childhood myositis in children were rarely positive. (4) Treatment and prognosis: besides bed rest and a reduction of physical activity, oseltamivir treatment, drugs to improve energy metabolism, fluid replacement and alkalinization of symptomatic treatment. All children had a good prognosis without sequelae.
CONCLUSIONS
This study summarized and analyzed the clinical characteristics of acute benign myositis associated with influenza A infection in children with the aim of allowing rapid and early diagnosis of the disease and reducing unnecessary diagnostic tests and treatments. Closely monitoring myalgia and the muscle enzyme spectrum is recommended to exclude other neuromuscular and metabolic diseases.
Topics: Humans; Influenza, Human; Retrospective Studies; Myositis; Male; Child, Preschool; Female; Child; Influenza A virus; Adolescent; Infant; China; Prognosis; Creatine Kinase
PubMed: 38535510
DOI: 10.1097/INF.0000000000004320 -
Cells Mar 2024Understanding the role of biased G protein-coupled receptor (GPCR) agonism in receptor signaling may provide novel insights into the opposing effects mediated by...
Functional Selectivity of Cannabinoid Type 1 G Protein-Coupled Receptor Agonists in Transactivating Glycosylated Receptors on Cancer Cells to Induce Epithelial-Mesenchymal Transition Metastatic Phenotype.
Understanding the role of biased G protein-coupled receptor (GPCR) agonism in receptor signaling may provide novel insights into the opposing effects mediated by cannabinoids, particularly in cancer and cancer metastasis. GPCRs can have more than one active state, a phenomenon called either 'biased agonism', 'functional selectivity', or 'ligand-directed signaling'. However, there are increasing arrays of cannabinoid allosteric ligands with different degrees of modulation, called 'biased modulation', that can vary dramatically in a probe- and pathway-specific manner, not from simple differences in orthosteric ligand efficacy or stimulus-response coupling. Here, emerging evidence proposes the involvement of CB1 GPCRs in a novel biased GPCR signaling paradigm involving the crosstalk between neuraminidase-1 (Neu-1) and matrix metalloproteinase-9 (MMP-9) in the activation of glycosylated receptors through the modification of the receptor glycosylation state. The study findings highlighted the role of CB1 agonists AM-404, Aravnil, and Olvanil in significantly inducing Neu-1 sialidase activity in a dose-dependent fashion in RAW-Blue, PANC-1, and SW-620 cells. This approach was further substantiated by findings that the neuromedin B receptor inhibitor, BIM-23127, MMP-9 inhibitor, MMP9i, and Neu-1 inhibitor, oseltamivir phosphate, could specifically block CB1 agonist-induced Neu-1 sialidase activity. Additionally, we found that CB1 receptors exist in a multimeric receptor complex with Neu-1 in naïve, unstimulated RAW-Blue, PANC-1, and SW-620 cells. This complex implies a molecular link that regulates the interaction and signaling mechanism among these molecules present on the cell surface. Moreover, the study results demonstrate that CB1 agonists induce NFκB-dependent secretory alkaline phosphatase (SEAP) activity in influencing the expression of epithelial-mesenchymal markers, E-cadherin, and vimentin in SW-620 cells, albeit the impact on E-cadherin expression is less pronounced compared to vimentin. In essence, this innovative research begins to elucidate an entirely new molecular mechanism involving a GPCR signaling paradigm in which cannabinoids, as epigenetic stimuli, may traverse to influence gene expression and contribute to cancer and cancer metastasis.
Topics: Cannabinoid Receptor Agonists; Matrix Metalloproteinase 9; Vimentin; Ligands; Glycosylation; Neuraminidase; Receptors, G-Protein-Coupled; Cannabinoids; Epithelial-Mesenchymal Transition; Cadherins; Neoplasms
PubMed: 38534324
DOI: 10.3390/cells13060480 -
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 -
European Journal of Medicinal Chemistry Apr 2024Inspired by our earlier findings regarding neuraminidase (NA) inhibitors interacting with 150-cavity or 430-cavity of NA, sixteen novel polyheterocyclic NA inhibitors...
Inspired by our earlier findings regarding neuraminidase (NA) inhibitors interacting with 150-cavity or 430-cavity of NA, sixteen novel polyheterocyclic NA inhibitors with 1,3,4-oxadiazole thioetheramide as core backbone were designed and synthesized based on the lead compound ZINC13401480. Of the synthesized compounds, compound N5 targeting 150-cavity exerts the best inhibitory activity against the wild-type H5N1 NA, with IC value of 0.14 μM, which is superior to oseltamivir carboxylate (OSC) (IC = 0.31 μM). Compound N10 targeting 430-cavity exhibits the best activity against the H5N1-H274Y mutant NA. Although the activity of N10 is comparable to that of OSC for wild-type H5N1 inhibition, it is approximately 60-fold more potent than OSC against the H274Y mutant, suggesting that it is not easy for the virus to develop drug resistance and is attractive for drug development. N10 (EC = 0.11 μM) also exhibits excellent antiviral activity against H5N1, which is superior to the positive control OSC (EC = 1.47 μM). Molecular docking study shows that the occupation of aromatic fused rings and oxadiazole moiety at the active site and the extension of the substituted phenyl to the 150-cavity or 430-cavity make great contributions to the good potency of this series of polyheterocyclic NA inhibitors. Some advancements in the discovery of effective target-specific NA inhibitors in this study may offer some assistance in the development of more potent anti-influenza drugs.
Topics: Neuraminidase; Influenza A Virus, H5N1 Subtype; Molecular Docking Simulation; Antiviral Agents; Oseltamivir; Enzyme Inhibitors; Oxadiazoles; Drug Resistance, Viral
PubMed: 38518525
DOI: 10.1016/j.ejmech.2024.116305 -
Internal Medicine (Tokyo, Japan) Mar 2024Background Seasonal influenza affects healthcare demand. However, the efficacy of anti-influenza drugs, particularly among young patients at a low risk of complications,...
Background Seasonal influenza affects healthcare demand. However, the efficacy of anti-influenza drugs, particularly among young patients at a low risk of complications, has rarely been evaluated. Therefore, we evaluated the efficacy of anti-influenza drugs against seasonal influenza in healthy young and middle-aged adults. Methods A systematic review and network meta-analysis were conducted. The Cochrane Central Register of Controlled Trials and Medical Literature Analysis and Retrieval System Online were searched for original articles reporting double-blind, randomized controlled trials published up to the end of July 2023. Clinical trials that tested the efficacy of anti-influenza drugs in young and middle-aged patients with seasonal influenza were also included. The primary outcome was time to fever alleviation. The efficacy and adverse effects of these treatments were estimated using a Bayesian hierarchical random-effects model and a Markov chain Monte Carlo simulation. Results In total, 24 articles with 34 treatments and 8,949 individuals were included. Oseltamivir (300 mg/day for 5 days) showed the largest reduction in time to fever alleviation by -19.1 (95% confidence interval [CI]: -29.4, -10.7) h compared with a placebo. Baloxavir marboxil (40 mg/day) reduced the time to symptom alleviation by -28.2 (95% CI: -42.7, -13.7) h, and peramivir (300 mg/day) administered by intravenous infusion for 1 day reduced the time to resumption of usual activities by -43.5 (95% CI: -72.8, -14.2) h. Conclusion Several pharmaceutical treatments were able to reduce the recovery time for fever and symptom alleviation and resumption of usual activities in young and middle-aged adults with seasonal influenza without increasing the risk of complications.
PubMed: 38494721
DOI: 10.2169/internalmedicine.2100-23 -
Gene Jun 2024Liver cancer is one of the most lethal malignancies and sorafenib resistance is the main treatment obstacle for patients with advanced liver cancer. Developing drugs...
Lianhua Qingwen exerts anti-liver cancer effects and synergistic efficacy with sorafenib through PI3K/AKT pathway: Integrating network pharmacology, molecular docking, and experimental validation.
Liver cancer is one of the most lethal malignancies and sorafenib resistance is the main treatment obstacle for patients with advanced liver cancer. Developing drugs that sensitize liver cancer patients to sorafenib is of great importance. Lianhua Qingwen (LHQW), a sort of Traditional Chinese Medicine (TCM) approved by the Chinese Food and Drug Administration (CFDA), is reported to exert synergistic effects with oseltamivir against Influenza virus. However, whether LHQW could exhibit anti-liver cancer effects and enhance the efficacy of sorafenib against liver cancer have not been reported. In the present study, the potential anti-liver cancer effects of LHQW and its synergistic effects with sorafenib were investigated via applying network pharmacology, molecular docking, and in vitro experiments. An "ingredient-compound- target-liver cancer" network was constructed which included 12 ingredients, 164 compounds, and 402 targets. AKT1 was identified as the most hub gene and the PI3K/AKT pathway was revealed as the most enriched pathway. Subsequently, the molecular docking results showed that kaempferol, luteolin, and quercetin were screened as the top 3 compounds which showed the tightest binding to AKT1. Further, the in vitro experiments verified that LHQW significantly inhibited liver cancer cell proliferation and induced apoptosis. Western blot assays confirmed that LHQW could attenuate the PI3K/AKT pathway. Interestingly, LHQW showed a synergistic effect with sorafenib against liver cancer via reducing cell viability, inducing apoptosis, and down- regulating PI3K/AKT pathway. This study broadens the potential application of LHQW and provides insights for liver cancer treatment.
Topics: Humans; Molecular Docking Simulation; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Sorafenib; Network Pharmacology; Liver Neoplasms; Drugs, Chinese Herbal
PubMed: 38493972
DOI: 10.1016/j.gene.2024.148383 -
Cell Reports Mar 2024Pneumolysin (Ply) is an indispensable cholesterol-dependent cytolysin for pneumococcal infection. Although Ply-induced disruption of pneumococci-containing endosomal...
Pneumolysin (Ply) is an indispensable cholesterol-dependent cytolysin for pneumococcal infection. Although Ply-induced disruption of pneumococci-containing endosomal vesicles is a prerequisite for the evasion of endolysosomal bacterial clearance, its potent activity can be a double-edged sword, having a detrimental effect on bacterial survivability by inducing severe endosomal disruption, bactericidal autophagy, and scaffold epithelial cell death. Thus, Ply activity must be maintained at optimal levels. We develop a highly sensitive assay to monitor endosomal disruption using NanoBiT-Nanobody, which shows that the pneumococcal sialidase NanA can fine-tune Ply activity by trimming sialic acid from cell-membrane-bound glycans. In addition, oseltamivir, an influenza A virus sialidase inhibitor, promotes Ply-induced endosomal disruption and cytotoxicity by inhibiting NanA activity in vitro and greater tissue damage and bacterial clearance in vivo. Our findings provide a foundation for innovative therapeutic strategies for severe pneumococcal infections by exploiting the duality of Ply activity.
Topics: Humans; Neuraminidase; Streptococcus pneumoniae; Streptolysins; Pneumococcal Infections; Bacterial Proteins
PubMed: 38483905
DOI: 10.1016/j.celrep.2024.113962 -
Infectious Diseases and Therapy Apr 2024Influenza is a common, seasonal infectious disease with broad medical, economic, and social consequences. Real-world evidence on the effect of influenza treatment on...
INTRODUCTION
Influenza is a common, seasonal infectious disease with broad medical, economic, and social consequences. Real-world evidence on the effect of influenza treatment on household transmission and healthcare resource utilization is limited in outpatient settings in the USA. This study examined the real-world effectiveness of baloxavir vs oseltamivir in reducing influenza household transmission and healthcare resource utilization.
METHODS
This prospective electronic survey on patient-reported outcomes was conducted between October 2022 and May 2023 via CVS Pharmacy in the USA. Adult participants (≥ 18 years old) were eligible if they filled a prescription for baloxavir or oseltamivir at a CVS Pharmacy within 2 days of influenza symptom onset. Participant demographics, household transmission, and all-cause healthcare resource utilization were collected. Transmission and utilization outcomes were assessed using χ and Fisher exact tests.
RESULTS
Of 87,871 unique patients contacted, 1346 (1.5%) consented. Of 374 eligible patients, 286 (90 baloxavir- and 196 oseltamivir-treated patients) completed the survey and were included in the analysis. Mean age of participants was 45.4 years, 65.6% were female, and 86.7% were White. Lower household transmission was observed with baloxavir compared with oseltamivir therapy (17.8% vs 26.5%; relative risk = 0.67; 95% CI 0.41-1.11). Healthcare resource utilization, particularly emergency department visits (0.0% vs 4.6%), was also numerically lower in the baloxavir-treated group; no hospitalizations were reported in either cohort.
CONCLUSIONS
The findings from this real-world study suggest that antiviral treatment of influenza with baloxavir may decrease household transmission and reduce healthcare resource utilization compared with oseltamivir.
PubMed: 38483775
DOI: 10.1007/s40121-024-00937-y