A5062196470- Influenza Virus Research Studies
- Respiratory viral infections research
- interferon and immune responses
- SARS-CoV-2 and COVID-19 Research
- Viral Infections and Immunology Research
- RNA and protein synthesis mechanisms
- Animal Disease Management and Epidemiology
- COVID-19 Clinical Research Studies
- Virology and Viral Diseases
- Tuberculosis Research and Epidemiology
- Viral gastroenteritis research and epidemiology
- Animal Virus Infections Studies
- Mosquito-borne diseases and control
- HIV Research and Treatment
- Viral Infections and Vectors
- HIV/AIDS drug development and treatment
- Pneumonia and Respiratory Infections
- Malaria Research and Control
- Viral Infections and Outbreaks Research
- Immune Response and Inflammation
- Parvovirus B19 Infection Studies
- Long-Term Effects of COVID-19
- Monoclonal and Polyclonal Antibodies Research
- Computational Drug Discovery Methods
- Quinazolinone synthesis and applications
Shionogi (Japan)
2016-2025
Futaba (Japan)
2016-2025
University of Alabama at Birmingham
2012-2013
Astellas Pharma (Japan)
2011
Tokyo Medical University
2004-2005
Tohoku University
1996-2004
Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models A and B virus infections, including strains resistant to current antiviral agents.We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After dose-ranging (10 40 mg) placebo-controlled trial, we undertook placebo- oseltamivir-controlled trial single, weight-based doses...
Abstract Baloxavir acid (BXA), derived from the prodrug baloxavir marboxil (BXM), potently and selectively inhibits cap-dependent endonuclease within polymerase PA subunit of influenza A B viruses. In clinical trials, single doses BXM profoundly decrease viral titers as well alleviating symptoms. Here, we characterize impact on BXA susceptibility replicative capacity variant viruses detected in post-treatment monitoring studies. We find that I38T substitution is a major pathway for reduced...
Cap-dependent endonuclease (CEN) resides in the PA subunit of influenza virus and mediates critical "cap-snatching" step viral RNA transcription, which is considered to be a promising anti-influenza target. Here, we describe vitro characterization novel CEN inhibitor, baloxavir acid (BXA), active form marboxil (BXM). BXA inhibits transcription via selective inhibition activity enzymatic assays, replication infected cells without cytotoxicity cytopathic effect assays. The antiviral also...
Single-dose baloxavir rapidly reduces influenza virus titers and symptoms in patients with uncomplicated influenza, but viruses reduced vitro susceptibility due to amino acid substitutions at position 38 of polymerase acidic protein (PA/I38X) sometimes emerge.We evaluated the kinetics, risk factors, effects on clinical virologic outcomes emergence PA/I38X-substituted viruses.Viruses containing PA/I38X were identified 3-9 days after treatment 9.7% (36/370) patients, whom 85.3% had transient...
In parallel with vaccination, oral antiviral agents are highly anticipated to act as countermeasures for the treatment of coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome 2 (SARS-CoV-2). Oral medication demands not only high activity but also target specificity, favorable bioavailability, and metabolic stability. Although a large number compounds have been identified potential inhibitors SARS-CoV-2 infection in vitro, few proven be effective vivo....
We assessed the safety and effectiveness of baloxavir marboxil administration in Japanese children with influenza.This open-label study administered 1 weight-adjusted dose to 107 aged 1-11 years laboratory-confirmed, febrile influenza virus infection ≤48 hours duration.Adverse events (AEs) were reported 34.6% patients, most commonly vomiting (7.5%); no serious AEs or causing discontinuation occurred. The median time alleviation illness was 44.6 (95% confidence interval, 38.9-62.5 hours),...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become established in the human population, making need to develop safe and effective treatments critical. We have developed small-molecule antiviral ensitrelvir, which targets 3C-like (3CL) protease of SARS-CoV-2. This study evaluated vitro vivo efficacy ensitrelvir compared with that another SARS-CoV-2 3CL PI, nirmatrelvir.
Baloxavir marboxil (formerly S-033188) is a first-in-class, orally available, cap-dependent endonuclease inhibitor licensed in Japan and the USA for treatment of influenza virus infection. We evaluated efficacy delayed oral with baloxavir combination neuraminidase mouse model lethal infection.The inhibitory potency acid (the active form marboxil) inhibitors was tested vitro. The therapeutic effects oseltamivir phosphate, or combinations thereof, were mice lethally infected A/PR/8/34;...
Survivin, an apoptotic inhibitor, is overexpressed in the majority of human tumor types and represents a novel target for anticancer therapy. Taxanes induce mitotic cell-cycle block through inhibition microtubule depolymerization, with subsequent elevated expression/stabilization survivin. We investigated administration survivin suppressant YM155 monobromide (YM155), combination docetaxel, non-small-cell lung cancer (NSCLC) xenograft model. Animals received 7-day continuous infusion YM155, 2...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiological agent of disease 2019 (COVID-19) and a devastating worldwide health concern. Development safe effective treatments not only important for interventions during current pandemic, but also providing general treatment options moving forward. We have developed ensitrelvir, an antiviral compound that targets 3C-like protease SARS-CoV-2. In this study, delayed-treatment mouse model was used to clarify potential in vivo...
<title>Abstract</title> Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a threat to public health and the economy. Although several SARS-CoV-2 vaccines exist, they have failed elicit effective neutralizing antibody responses against emerging variants harboring spike protein mutations. Moreover, while certain neutralizing-antibody-based therapies were in early stages of pandemic, their performance declined with emergence Thus, it is...
Baloxavir marboxil (BXM) is an orally available small molecule inhibitor of cap-dependent endonuclease (CEN), essential enzyme in the initiation mRNA synthesis influenza viruses. In present study, we evaluated efficacy BXM against virus infection mouse models. Single-day oral administration completely prevented mortality due to with A and B mice. Moreover, 5-day repeated was more effective for reducing body weight loss mice infected than oseltamivir phosphate (OSP), even when treatment...
Influenza viruses cause seasonal outbreaks and pose a continuous pandemic threat. Although vaccines are available for influenza control, their efficacy varies each season vaccine novel virus manufactured using current technology will not be fast enough to mitigate the effect of first wave. Antivirals can effective against many different but have thus far been used extensively outbreak control. Baloxavir, recently licensed antiviral drug that targets endonuclease, has shown reduce shedding...
Baloxavir is approved in several countries for the treatment of uncomplicated influenza otherwise-healthy and high-risk patients. Treatment-emergent viruses with reduced susceptibility to baloxavir have been detected clinical trials, but likelihood widespread occurrence depends on replication capacity onward transmission. We evaluated fitness A/H3N2 A/H1N1pdm09 polymerase acidic (PA) I38T-variant conferring relative wild-type (WT) viruses, using a competitive mixture ferret model,...
Despite the clinical relevance of latent HIV-1 infection as a block to eradication, molecular biology latency remains incompletely understood. We recently demonstrated presence gatekeeper kinase function that controls infection. Using array analysis, we here expand on this finding and demonstrate activity profile latently HIV-1-infected T cells is altered relative uninfected cells. A ranking kinases generated from these kinome data predicted PIM-1 key switch involved in control. genetic...
Abstract Background Baloxavir marboxil (BXM), an oral selective cap-dependent endonuclease inhibitor, is effective and safe for treating acute influenza in otherwise healthy patients. Method We conducted international, randomized, double-blind, placebo (PLC)- oseltamivir (Os)-controlled treatment study patients at higher risk (HR) of complications. Inclusion criteria included age ≥12 years, fever + symptoms ≤48 hours duration, presence least 1 HR factor adapted from CDC criteria. Patients...
Abstract Human infections with avian-origin influenza A(H7N9) virus represent a serious threat to global health; however, treatment options are limited. Here, we show the inhibitory effects of baloxavir acid (BXA) and its prodrug marboxil (BXM), first-in-class cap-dependent endonuclease inhibitor, against A(H7N9), in vitro vivo . In cell culture, BXA at four nanomolar concentration achieved 1.5–2.8 log reduction titers including NA-R292K mutant highly pathogenic avian viruses, whereas NA...
The medicinal chemistry and structure-activity relationships (SAR) for a novel series of carbamoyl pyridone bicycle (CAB) compounds as influenza Cap-dependent endonuclease (CEN) inhibitors are disclosed. Substituent effects were evaluated at the C (N)-1, N-3, C-7 positions CAB ring system using docking study. Submicromolar EC50 values achieved in cellular assay with C-7-unsubstituted which possessed benzhydryl group on either C-1 or N-1 position. An N-3 substituent was found to be critical...
Abstract Background Baloxavir marboxil (BXM) is an approved drug that selectively targets cap‐dependent endonuclease on PA subunit in the RNA polymerase complex of influenza A and B viruses. Amino acid substitutions at position 38 were identified as a major pathway for reduced susceptibility to baloxavir (BXA), active form BXM. Additionally, found positions E23, A37, E199 impact BXA by less than 10‐fold. Methods We comprehensively evaluated novel amino PA, PB1, PB2 subunits BXM clinical...
Human infections caused by the H5 highly pathogenic avian influenza virus (HPAIV) sporadically threaten public health. The susceptibility of HPAIVs to baloxavir acid (BXA), a new class inhibitors for cap-dependent endonuclease, has been confirmed in vitro, but it not yet fully characterized. Here, efficacy BXA against HPAIVs, including recent H5N8 variants, was assessed vitro. antiviral marboxil (BXM) H5N1 virus-infected mice also investigated. exhibited similar vitro activities H5N1, H5N6,...
ABSTRACT Despite its clinical importance, the molecular biology of HIV-1 latency control is at best partially understood, and literature remains conflicting. The most recent description that latent integrated into actively expressed host genes has further confounded situation. This lack understanding complicates our efforts to identify therapeutic compounds or strategies could reactivate infection in patients, a prerequisite for eradication infection. Currently, many development operate...
Abstract In parallel with vaccination, oral antiviral agents are highly anticipated to act as countermeasures for the treatment of coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Oral medication demands not only high activity but also target specificity, favorable bioavailability, and metabolic stability. Although a large number compounds have been identified potential inhibitors SARS-CoV-2 infection in vitro , few proven...