A phase 1, open-label, randomized, 2-way crossover study to assess the effects of acid reducing agent(s) on the pharmacokinetics of a single oral dose of JNJ-64417184 in healthy adult participants - Drug-drug Interaction of Multiple-dose JNJ-64417184

开始日期2020-07-21

申办/合作机构

Janssen-Cilag International NV

NCT04453189

/ Completed临床1期

A Phase 1, Open-label, Randomized, 2-Way Crossover Study to Assess the Effects of Acid-Reducing Agent(s) on the Pharmacokinetics of a Single Oral Dose of JNJ-64417184 in Healthy Adult Participants

The primary purpose of this study is to evaluate the effect of multiple-dose administration of lansoprazole on the single-dose pharmacokinetics (PK) of JNJ-64417184 in healthy adult participants; and to evaluate the effect of time-separated, multiple-dose administration of famotidine on the single-dose PK of JNJ-64417184 in healthy adult participants (optional).

开始日期2020-07-20

申办/合作机构

Janssen Research & Development LLC

NCT04426357

/ Terminated临床1期

A Single-dose, Open-label, Parallel-group Study to Evaluate the Effect of Renal Impairment on the Pharmacokinetics of JNJ-64417184 and Its Two Minor Metabolites JNJ-68294291 and JNJ-65201526 in Adult Participants

The main purpose of this study is to evaluate the pharmacokinetics of JNJ-64417184, JNJ-68294291, and JNJ-65201526 after a single oral dose of JNJ-64417184 in adult participants with various degrees of impaired renal function (moderate [optional], severe renal impairment, and end stage renal disease (ESRD) not requiring hemodialysis) compared to participants with normal renal function.

开始日期2020-07-03

申办/合作机构

Janssen Pharmaceutica NV

100 项与 RSV polymerase 相关的临床结果

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100 项与 RSV polymerase 相关的转化医学

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0 项与 RSV polymerase 相关的专利（医药）

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项与 RSV polymerase 相关的文献（医药）

2024-07-11·Journal of Medicinal Chemistry

Spiro-Azetidine Oxindoles as Long-Acting Injectables for Pre-Exposure Prophylaxis against Respiratory Syncytial Virus Infections

Article

作者: Stoops, Bart ; Jacoby, Edgar ; De Bruyn, Suzanne ; Jacobs, Tom ; Kesteleyn, Bart ; Nájera, Isabel ; Lammens, Lieve ; Van Den Berg, Joke ; De Zwart, Loeckie ; Shaffer, Paul ; Martinez Lamenca, Carolina ; Herschke, Florence ; Matcha, Kiran ; Darville, Nicolas ; Roymans, Dirk ; Hache, Geerwin ; Ysebaert, Nina ; Milligan, Cynthia ; Lecomte, Morgan ; Coesemans, Erwin ; Pieters, Serge ; Jonckers, Tim H. M. ; Demin, Samuel ; Rigaux, Peter ; Hu, Lili ; Van Rompaey, Dries ; Abeywickrema, Pravien

Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants, the elderly, and immune-compromised patients. While a half-life extended monoclonal antibody and 2 vaccines have recently been approved for infants and the elderly, respectively, options to prevent disease in immune-compromised patients are still needed. Here, we describe spiro-azetidine oxindoles as small molecule RSV entry inhibitors displaying favorable potency, developability attributes, and long-acting PK when injected as an aqueous suspension, suggesting their potential to prevent complications following RSV infection over a period of 3 to 6 months with 1 or 2 long-acting intramuscular (IM) or subcutaneous (SC) injections in these immune-compromised patients.

2021-07-01·Cell Reports1区 · 生物学

A safe and effective mucosal RSV vaccine in mice consisting of RSV phosphoprotein and flagellin variant

1区 · 生物学

ArticleOA

作者: Zhao, Bali ; Liu, Bowen ; Yang, Yi ; Zhang, Yue ; He, Bing ; Yan, Hu ; Jiang, Shibo ; Zhou, Dihan ; Fan, Xuxu ; Yan, Huimin ; Liu, Shuning ; Li, Xian ; Chen, Yao-Qing ; Zhang, Fan ; Zhang, Ejuan ; Yang, Jingyi ; Zhong, Maohua

Respiratory syncytial virus (RSV) is a major cause of serious acute lower respiratory tract infection in infants and the elderly. The lack of a licensed RSV vaccine calls for the development of vaccines with other targets and vaccination strategies. Here, we construct a recombinant protein, designated P-KFD1, comprising RSV phosphoprotein (P) and the E.-coli-K12-strain-derived flagellin variant KFD1. Intranasal immunization with P-KFD1 inhibits RSV replication in the upper and lower respiratory tract and protects mice against lung disease without vaccine-enhanced disease (VED). The P-specific CD4⁺ T cells provoked by P-KFD1 intranasal (i.n.) immunization either reside in or migrate to the respiratory tract and mediate protection against RSV infection. Single-cell RNA sequencing (scRNA-seq) and carboxyfluorescein succinimidyl ester (CFSE)-labeled cell transfer further characterize the Th1 and Th17 responses induced by P-KFD1. Finally, we find that anti-viral protection depends on either interferon-γ (IFN-γ) or interleukin-17A (IL-17A). Collectively, P-KFD1 is a promising safe and effective mucosal vaccine candidate for the prevention of RSV infection.

2005-10-15·Journal of Virology2区 · 医学

Inhibitors of Respiratory Syncytial Virus Replication Target Cotranscriptional mRNA Guanylylation by Viral RNA-Dependent RNA Polymerase

2区 · 医学

Article

作者: Fazal, Gulrez ; Scouten, Erika ; Whitehead, Paul ; Bordeleau, Josée ; Lawetz, Carol ; Liuzzi, Michel ; Dô, Florence ; Simoneau, Bruno ; Bolger, Gordon ; Mason, Stephen W. ; Lamarre, Lyne ; Lapeyre, Nicole ; McCollum, Robert S. ; Dansereau, Nathalie ; Cartier, Mireille ; Massariol, Marie-Josée ; Rancourt, Jean ; Lagacé, Lisette ; Gaudette, Yvon ; Landry, Serge

ABSTRACTRespiratory syncytial virus (RSV) is a major cause of respiratory illness in infants, immunocompromised patients, and the elderly. New antiviral agents would be important tools in the treatment of acute RSV disease. RSV encodes its own RNA-dependent RNA polymerase that is responsible for the synthesis of both genomic RNA and subgenomic mRNAs. The viral polymerase also cotranscriptionally caps and polyadenylates the RSV mRNAs at their 5′ and 3′ ends, respectively. We have previously reported the discovery of the first nonnucleoside transcriptase inhibitor of RSV polymerase through high-throughput screening. Here we report the design of inhibitors that have improved potency both in vitro and in antiviral assays and that also exhibit activity in a mouse model of RSV infection. We have isolated virus with reduced susceptibility to this class of inhibitors. The mutations conferring resistance mapped to a novel motif within the RSV L gene, which encodes the catalytic subunit of RSV polymerase. This motif is distinct from the catalytic region of the L protein and bears some similarity to the nucleotide binding domain within nucleoside diphosphate kinases. These findings lead to the hypothesis that this class of inhibitors may block synthesis of RSV mRNAs by inhibiting guanylylation of viral transcripts. We show that short transcripts produced in the presence of inhibitor in vitro do not contain a 5′ cap but, instead, are triphosphorylated, confirming this hypothesis. These inhibitors constitute useful tools for elucidating the molecular mechanism of RSV capping and represent valid leads for the development of novel anti-RSV therapeutics.

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