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Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV).

ABSTRACT: The search for novel therapeutic interventions for viral disease is a challenging pursuit, hallmarked by the paucity of antiviral agents currently prescribed. Targeting of viral proteins has the inextricable challenge of rise of resistance. Safe and effective vaccines are not possible for many viral pathogens. New approaches are required to address the unmet medical need in this area. We undertook a cell-based high-throughput screen to identify leads for development of drugs to treat respiratory syncytial virus (RSV), a serious pediatric pathogen. We identified compounds that are potent (nanomolar) inhibitors of RSV in vitro in HEp-2 cells and in primary human bronchial epithelial cells and were shown to act postentry. Interestingly, two scaffolds exhibited broad-spectrum activity among multiple RNA viruses. Using the chemical matter as a probe, we identified the targets and identified a common cellular pathway: the de novo pyrimidine biosynthesis pathway. Both targets were validated in vitro and showed no significant cell cytotoxicity except for activity against proliferative B- and T-type lymphoid cells. Corollary to this finding was to understand the consequences of inhibition of the target to the host. An in vivo assessment for antiviral efficacy failed to demonstrate reduced viral load, but revealed microscopic changes and a trend toward reduced pyrimidine pools and findings in histopathology. We present here a discovery program that includes screen, target identification, validation, and druggability that can be broadly applied to identify and interrogate other host factors for antiviral effect starting from chemical matter of unknown target/mechanism of action.

SUBMITTER: Bonavia A

PROVIDER: S-EPMC3084118 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV).

Bonavia Aurelio A Franti Michael M Pusateri Keaney Erin E Kuhen Kelli K Seepersaud Mohindra M Radetich Branko B Shao Jian J Honda Ayako A Dewhurst Janetta J Balabanis Kara K Monroe James J Wolff Karen K Osborne Colin C Lanieri Leanne L Hoffmaster Keith K Amin Jakal J Markovits Judit J Broome Michelle M Skuba Elizabeth E Cornella-Taracido Ivan I Joberty Gerard G Bouwmeester Tewis T Hamann Lawrence L Tallarico John A JA Tommasi Ruben R Compton Teresa T Bushell Simon M SM

Proceedings of the National Academy of Sciences of the United States of America 20110418 17

The search for novel therapeutic interventions for viral disease is a challenging pursuit, hallmarked by the paucity of antiviral agents currently prescribed. Targeting of viral proteins has the inextricable challenge of rise of resistance. Safe and effective vaccines are not possible for many viral pathogens. New approaches are required to address the unmet medical need in this area. We undertook a cell-based high-throughput screen to identify leads for development of drugs to treat respiratory ...[more]

PMID: 21502533

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Project description:Respiratory Syncytial Virus (RSV) is the most common cause of respiratory tract infection in infants and children and shows increasing trend among elderly people worldwide. In many developing country settings, population and household structures have gone through some significant changes in the past decades, namely fewer births, more elderly population, and smaller household size but more RSV high-risk individuals. These dynamics have been captured in a mathematical model with RSV transmission dynamics to predict the disease burden on the detailed population for future targeted interventions. The population and disease dynamics model was constructed and tested against the hospitalization data for Acute Lower Respiratory Tract Infection due to RSV in rural Thai settings between 2005 and 2011. The proportion of extended families is predicted to increase by about 10% from 2005 to 2020, especially for those with elderly population, while the classic nuclear family type (with adults and children) will decline by about 10%. For RSV, infections from extended family type (approximately 60% of all household types) have majorly contributed to the force of infection (FOI). While the model predicted the increase of FOI from the extended family by 15% from 2005 to 2020, the FOI contributed by other household types would be either stable or decrease in the same time period. RSV incidence rate is predominantly high among babies (92.2%) and has been predicted to decrease slightly over time (from 940 to 864 cases per 100,000 population by 2020), while the incidence rates among children and elderly people may remain steadily low over the same period. However, the estimated incidence rates among elderly people were twice than those in children. The model predicts that approximately 60% of FOI for RSV will come from members of the extended family type. The incidence rate of RSV among children and elderly in extended families was about 20 times lower than that in infants and the trend is steady. Targeted intervention strategies, such as health education in some specific groups and targeted vaccination, may be considered, with the focus on extended family type. Target interventions on babies can lessen the transmission to children and elderly especially when transmission within households of extended family type is high.

Dataset Information

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV).

Publications

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV).

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