Identification of Pyrimidine Biosynthesis Inhibitors with Broad Spectrum Antiviral Activity and Assessment of the Druggability of this Pathway for Efficacy against RSV
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Bonavia, Aurelio, Franti, Michael, Keaney, Erin, Kuhen, Kelli, Seepersaud, Mohindra, Radetich, Branko, Shao, Jian, Honda, Ayako, Dewhurst, Janetta, Balabanis, Kara, Monroe, James, Wolff, Karen, Osborne, Colin, Bourque, Leanne, Hoffmaster, Keith, Amin, Jakal, Markovits, Judit, Broome, Michelle, Skuba, Elizabeth, Cornella-Taracido, Ivan, Joberty, Gerard, Bouwmeester, Antonius, Hamann, Lawrence, Tallarico, John, Tommasi, Ruben, Compton, Teresa and Bushell, Simon (2011) Identification of Pyrimidine Biosynthesis Inhibitors with Broad Spectrum Antiviral Activity and Assessment of the Druggability of this Pathway for Efficacy against RSV. Proceedings of the National Accademy of Sciences USA, 108 (17). pp. 6739-6744. ISSN 0027-8424
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 (nM) inhibitors of RSV in vitro in HEp-2 cells and in primary human bronchial epithelial cells and were shown to act post-entry. 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 towards 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/MoA.
| Item Type: | Article |
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| Date Deposited: | 13 Oct 2015 13:15 |
| Last Modified: | 13 Oct 2015 13:15 |
| URI: | https://oak.novartis.com/id/eprint/3982 |