YM-53403, a unique anti-respiratory syncytial virus agent with a novel mechanism of action

Sudo, Kenji; Miyazaki, Y.; Kojima, Naoko; Kobayashi, Masayuki; Suzuki, Hiroshi; Shintani, Masafumi; Shimizu, Yoshiyuki

doi:10.1016/j.antiviral.2004.12.002

Cited by 73 publications

(63 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several direct-acting, small-molecule inhibitors targeting different steps of the RSV life cycle were tested, including TMC-353121, an entry inhibitor targeting the RSV fusion protein (13); RSV-604, an early postentry inhibitor binding a conserved region of the nucleocapsid protein (14,15); YM-53403, an inhibitor targeting the RSV polymerase in variable region 2 (16); and BI-D, an inhibitor targeting the RSV polymerase in domain V (17). The mechanisms of inhibition by RSV-604 and YM-53403…”

mentioning

confidence: 99%

The Interferon Type I/III Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells Can Be Attenuated or Amplified by Antiviral Treatment

McCutcheon

Jordan

Mawhorter

et al. 2016

J Virol

View full text Add to dashboard Cite

Human respiratory syncytial virus (RSV) is a single-stranded RNA virus that causes acute, and occasionally fatal, lower respiratory illness in young infants, the elderly, and immunocompromised patients. Therapeutic interventions able to cut short viral replication and quickly return the airways to normal function are needed. An understanding of antiviral activities and their effects on host defense mechanisms is important for the design of safe and effective therapy. We targeted functionally and temporally distinct steps within the viral life cycle using small-molecule RSV inhibitors and studied their antiviral activities and their effects on innate interferon responses of airway epithelial cells in vitro. H uman respiratory syncytial virus (RSV) is a single-stranded, negative-sense RNA virus belonging to the family Paramyxoviridae. Premature and very young infants are at the highest risk of having severe lower respiratory tract infections and, later, a higher incidence of chronic asthma (1). Older adults with chronic lung or heart disease and individuals with suppressed immune systems also often require medical care after RSV infection. The lack of long-lasting protection after primary infection contributes to the capacity of RSV to cause yearly outbreaks and has challenged vaccine development (2). Synagis, a monoclonal antibody (MAb) directed against the RSV fusion protein, has shown prophylactic utility, but its cost and intramuscular route of administration have limited its use to hospitalized, high-risk infants Ͻ2 years of age (2). The only therapeutic intervention for RSV infection currently available to patients is the use of ribavirin (3), but its use is also limited because of poor efficacy and teratogenicity and the requirement of an aerosol and/or intravenous (i.v.) mode of administration in hospital settings (4). New therapeutic interventions able to lower the viral load, decrease transmission, and prevent lower respiratory complications are needed.RSV infection is initiated by attachment of the viral G protein to the surface of airway epithelial (AE) cells (5,6). Following attachment, the viral F protein mediates fusion of the viral and cellular membranes, allowing the RSV ribonucleic protein (RNP) complex, comprised of the viral RNA genome encapsulated with nucleoprotein (N) and associated with the phosphoprotein (P) and RNA-dependent RNA polymerase (L), to enter the cytoplasm. The RNP complex performs viral transcription to produce capped and polyadenylated mRNAs and genome replication. Detailed understanding of RSV biology is made difficult by the intimate coupling of transcription and replication activities. Furthermore, the RSV polymerase is large and complex, containing multiple domains and enzymatic activities that allow it to function and be

show abstract

mentioning

confidence: 99%

The Interferon Type I/III Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells Can Be Attenuated or Amplified by Antiviral Treatment

McCutcheon

Jordan

Mawhorter

et al. 2016

J Virol

View full text Add to dashboard Cite

show abstract

“…Yamanouchi patents and publications have described a series of benzazepine thiophenes with submicromolar activity in plaque-reduction assays against RSV [60]. One of the most potent compounds, YM53403 (Figure 7), had an EC 50 of 200 nM with a selectivity index of over 400.…”

Section: Replication Inhibitors: Benzazepine Inhibitorsmentioning

confidence: 99%

The Prophylaxis and Treatment with Antiviral Agents of Respiratory Syncytial Virus Infections

Najarro¹,

Angell

Powell³

2012

Antivir Chem Chemother

View full text Add to dashboard Cite

show abstract

“…6 There are a number of antiviral RSV approaches, 7 including YM-53403, a small molecule that targets the RSV L (polymerase) protein, required for transcription and replication of the RSV genome. 8 Although there are a number of clinical vaccine studies currently taking place, 9 there are at present no licensed vaccines for RSV. The aim of this study was to screen the AstraZeneca chemical diversity collection to identify small-molecule inhibitors of RSV.…”

Section: High-throughput Hit Screening Cascade To Identify Respiratormentioning

confidence: 99%

High-Throughput Hit Screening Cascade to Identify Respiratory Syncytial Virus (RSV) Inhibitors

et al. 2015

View full text Add to dashboard Cite

Respiratory syncytial virus (RSV) infects 99% of children by age 2 years and is a leading cause of serious lower respiratory tract infection (LRTI) and infant hospitalization in the United Kingdom. Identification of efficacious RSV therapeutics has been hindered by the lack of a robust and appropriate primary assay for high-throughput screening (HTS). Here we report an HTS cascade that identified inhibitors of RSV replication using a robust RSV replicon luminescence-reporter assay for the primary campaign. The performance of the assay was consistent and reliable at scale, with Z′ of 0.55 ± 0.08 across 150 assay plates and signal-to-background ratios >40. The HTS assay was used to screen the AstraZeneca compound library of 1 million compounds at a single concentration of 10 µM. Hits specifically targeting the RSV replicon were determined using a series of hit generation assays. Compounds nonspecifically causing cell toxicity were removed, and hits were confirmed in live viral inhibition assays exhibiting greater physiological relevance than the primary assay. In summary, we developed a robust screening cascade that identified hit molecules that specifically targeted RSV replication.

show abstract

YM-53403, a unique anti-respiratory syncytial virus agent with a novel mechanism of action

Cited by 73 publications

References 35 publications

The Interferon Type I/III Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells Can Be Attenuated or Amplified by Antiviral Treatment

The Interferon Type I/III Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells Can Be Attenuated or Amplified by Antiviral Treatment

The Prophylaxis and Treatment with Antiviral Agents of Respiratory Syncytial Virus Infections

High-Throughput Hit Screening Cascade to Identify Respiratory Syncytial Virus (RSV) Inhibitors

Contact Info

Product

Resources

About