Non-benzimidazole containing inhibitors of respiratory syncytial virus

Pryde, David C.; Tran, Thien Duc; Gardner, Iain; Bright, Helen; Stupple, Paul A.; Galan, Sébastien R. G.; Alsop, Liam; Watson, Lesa; Middleton, Donald S.; Dayal, Satish; Platts, Michelle; Murray, Edward J.; Parkinson, Tanya; Webster, Robert O.

doi:10.1016/j.bmcl.2012.11.062

Cited by 7 publications

(7 citation statements)

References 24 publications

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“…Pfizer reported imidazole-based inhibitors of RSV fusion ( 11 - 1 , Figure ). The introduction of an aromatic group to the 4-position of the imidazole afforded modestly potent analogues with thiazole 11 - 1 orally bioavailable in rats ( F % = 34%). MedShine Discovery (Nanjing, China) have claimed a series of tetrahydrobenzimidazoles linked to spirocyclic oxindoles as inhibitors of RSV ( 11 - 2 ), whereas ReViral have described a series of monocyclic pyrimidines ( 11 - 3 ) .…”

Section: Preclinical Rsv Inhibitor Programsmentioning

confidence: 99%

State of the Art in Respiratory Syncytial Virus Drug Discovery and Development

2018

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Respiratory syncytial virus (RSV) is a globally prevalent viral infection with limited treatment options which hospitalizes millions each year. Treatment options have been limited to palivizumab, a monoclonal antibody, approved for prophylaxis in high-risk infants and ribavirin with very limited efficacy and significant safety concerns. This Perspective surveys the range of direct acting antiviral agents (DAAs) that target key steps in the viral life cycle. A number of approaches to DAAs have produced landmark clinical studies over the past few years, notably in fusion and nucleoside inhibitors, and an update of the clinical status of these compounds is provided. Non-nucleoside inhibitors of replication are reviewed in addition to inhibitors of other mechanisms, notably the RSV N and G proteins. This article will provide an informative perspective of the current status of drug discovery targeted at providing an effective therapy for RSV infection.

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Section: Preclinical Rsv Inhibitor Programsmentioning

confidence: 99%

State of the Art in Respiratory Syncytial Virus Drug Discovery and Development

2018

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“…However, this modification did not have much difference in the anti-viral activity, thus rendering this modification not much of practical use. There are several novel nonbenzimidazole based compounds, showing anti-RSV activity in vitro, but a more polar compound thiazoleimidazole 13 was selected on the compound potency, moderate permeability, and low metabolic rate in rats, and more detailed in vivo studies are further anticipated [183].…”

Section: Fusion Inhibitorsmentioning

confidence: 99%

Recent Advances in Diagnosis, Prevention, and Treatment of Human Respiratory Syncytial Virus

Bawage

Tiwari

Pillai

et al. 2013

Advances in Virology

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Human respiratory syncytial virus (RSV) is a common cause of respiratory infection in infants and the elderly, leading to significant morbidity and mortality. The interdisciplinary fields, especially biotechnology and nanotechnology, have facilitated the development of modern detection systems for RSV. Many anti-RSV compounds like fusion inhibitors and RNAi molecules have been successful in laboratory and clinical trials. But, currently, there are no effective drugs for RSV infection even after decades of research. Effective diagnosis can result in effective treatment, but the progress in both of these facets must be concurrent. The development in prevention and treatment measures for RSV is at appreciable pace, but the implementation into clinical practice still seems a challenge. This review attempts to present the promising diverse research approaches and advancements in the area of diagnosis, prevention, and treatment that contribute to RSV management.

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“…Existing prophylaxis and antiviral therapies for acute hRSV infections in infants are limited to a humanized monoclonal antibody that is reserved for use in high risk pediatric patients and ribavirin (Olszewska and Openshaw, 2009). Multiple potential antivirals are under clinical investigation Pryde et al, 2013;Yu et al, 2004Yu et al, , 2007, including two currently in clinical trials. These are a nucleoside RNA polymerase inhibitor AL-8176 (Wang et al, 2015) and a fusion inhibitor GS-5806 (Mackman et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Benzimidazole analogs inhibit respiratory syncytial virus G protein function

et al. 2015

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Human respiratory syncytial virus (hRSV) is a highly contagious Paramyxovirus that infects most children by age two, generating an estimated 75,000-125,000 hospitalizations in the U.S. annually. hRSV is the most common cause of bronchiolitis and pneumonia among infants and children under 1year of age, with significant mortality among high-risk groups. A regulatory agency-approved vaccine is not available, and existing prophylaxis and therapies are limited to use in high-risk pediatric patients; thus additional therapies are sorely needed. Here, we identify a series of benzimidazole analogs that inhibit hRSV infection in vitro with high potency, using a previously-reported high-throughput screening assay. The lead compound, SRI 29365 (1-[6-(2-furyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl]methyl-1H-benzimidazole), has an EC50 of 66μM and a selectivity >50. We identified additional compounds with varying potencies by testing commercially-available chemical analogs. Time-of-addition experiments indicated that SRI 29365 effectively inhibits viral replication only if present during the early stages of viral infection. We isolated a virus with resistance to SRI 29365 and identified mutations in the transmembrane domain of the viral G protein genomic sequence that suggested that the compound inhibits G-protein mediated attachment of hRSV to cells. Additional experiments with multiple cell types indicated that SRI 29365 antiviral activity correlates with the binding of cell surface heparin by full-length G protein. Lastly, SRI 29365 did not reduce hRSV titers or morbidity/mortality in efficacy studies using a cotton rat model. Although SRI 29365 and analogs inhibit hRSV replication in vitro, this work suggests that the G-protein may not be a valid drug target in vivo.

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Non-benzimidazole containing inhibitors of respiratory syncytial virus

Cited by 7 publications

References 24 publications

State of the Art in Respiratory Syncytial Virus Drug Discovery and Development

State of the Art in Respiratory Syncytial Virus Drug Discovery and Development

Recent Advances in Diagnosis, Prevention, and Treatment of Human Respiratory Syncytial Virus

Benzimidazole analogs inhibit respiratory syncytial virus G protein function

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