title: 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.
authors.affiliation: Novartis Institutes for Biomedical Research, Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Bonavia
authors.forename: Michael
authors.initials: M
authors.lastname: Franti
authors.forename: Erin
authors.initials: E
authors.lastname: Pusateri Keaney
authors.forename: Kelli
authors.initials: K
authors.lastname: Kuhen
authors.forename: Mohindra
authors.initials: M
authors.lastname: Seepersaud
authors.forename: Branko
authors.initials: B
authors.lastname: Radetich
authors.forename: Jian
authors.initials: J
authors.lastname: Shao
authors.forename: Ayako
authors.initials: A
authors.lastname: Honda
authors.forename: Janetta
authors.initials: J
authors.lastname: Dewhurst
authors.forename: Kara
authors.initials: K
authors.lastname: Balabanis
authors.forename: James
authors.initials: J
authors.lastname: Monroe
authors.forename: Karen
authors.initials: K
authors.lastname: Wolff
authors.forename: Colin
authors.initials: C
authors.lastname: Osborne
authors.forename: Leanne
authors.initials: L
authors.lastname: Lanieri
authors.forename: Keith
authors.initials: K
authors.lastname: Hoffmaster
authors.forename: Jakal
authors.initials: J
authors.lastname: Amin
authors.forename: Judit
authors.initials: J
authors.lastname: Markovits
authors.forename: Michelle
authors.initials: M
authors.lastname: Broome
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Skuba
authors.forename: Ivan
authors.initials: I
authors.lastname: Cornella-Taracido
authors.forename: Gerard
authors.initials: G
authors.lastname: Joberty
authors.forename: Tewis
authors.initials: T
authors.lastname: Bouwmeester
authors.forename: Lawrence
authors.initials: L
authors.lastname: Hamann
authors.forename: John A
authors.initials: JA
authors.lastname: Tallarico
authors.forename: Ruben
authors.initials: R
authors.lastname: Tommasi
authors.forename: Teresa
authors.initials: T
authors.lastname: Compton
authors.forename: Simon M
authors.initials: SM
authors.lastname: Bushell
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D012136:Respiratory Syncytial Viruses / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D014709:Vero Cells
chemical_list: D000998:Antiviral Agents