title: Discovery of β-D-2'-deoxy-2'-α-fluoro-4'-α-cyano-5-aza-7,9-dideaza adenosine as a potent nucleoside inhibitor of respiratory syncytial virus with excellent selectivity over mitochondrial RNA and DNA polymerases.
abstract: Novel 4'-substituted β-d-2'-deoxy-2'-α-fluoro (2'd2'F) nucleoside inhibitors of respiratory syncytial virus (RSV) are reported. The introduction of 4'-substitution onto 2'd2'F nucleoside analogs resulted in compounds demonstrating potent cell based RSV inhibition, improved inhibition of the RSV polymerase by the nucleoside triphosphate metabolites, and enhanced selectivity over incorporation by mitochondrial RNA and DNA polymerases. Selectivity over the mitochondrial polymerases was found to be extremely sensitive to the specific 4'-substitution and not readily predictable. Combining the most potent and selective 4'-groups from N-nucleoside analogs onto a 2'd2'F C-nucleoside analog resulted in the identification of β-D-2'-deoxy-2'-α-fluoro-4'-α-cyano-5-aza-7,9-dideaza adenosine as a promising nucleoside lead for RSV.
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, United States.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Clarke
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, United States. Electronic address: rmackman@gilead.com.
authors.forename: Richard
authors.initials: R
authors.lastname: Mackman
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Byun
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, United States.
authors.forename: Hon
authors.initials: H
authors.lastname: Hui
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, United States.
authors.forename: Ona
authors.initials: O
authors.lastname: Barauskas
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, United States.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Birkus
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, United States.
authors.forename: Byoung-Kwon
authors.initials: BK
authors.lastname: Chun
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, United States.
authors.forename: Edward
authors.initials: E
authors.lastname: Doerffler
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, United States.
authors.forename: Joy
authors.initials: J
authors.lastname: Feng
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, United States.
authors.forename: Kapil
authors.initials: K
authors.lastname: Karki
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, United States.
authors.forename: Gary
authors.initials: G
authors.lastname: Lee
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, United States.
authors.forename: Michel
authors.initials: M
authors.lastname: Perron
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, United States.
authors.forename: Dustin
authors.initials: D
authors.lastname: Siegel
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, United States.
authors.forename: Swami
authors.initials: S
authors.lastname: Swaminathan
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, United States.
authors.forename: William
authors.initials: W
authors.lastname: Lee
mesh_terms: D000241:Adenosine / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001372:Aza Compounds / Q000737:chemistry; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D019384:Nucleic Acid Synthesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012313:RNA / Q000737:chemistry* / Q000378:metabolism; D000077278:RNA, Mitochondrial; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012136:Respiratory Syncytial Viruses / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001372:Aza Compounds; D019384:Nucleic Acid Synthesis Inhibitors; D000077278:RNA, Mitochondrial; D012313:RNA; D012324:RNA-Dependent RNA Polymerase; D004259:DNA-Directed DNA Polymerase; D000241:Adenosine
keywords: DNA polymerase γ; Mitochondria; Mitochondrial RNA polymerase; Nucleoside; Respiratory syncytial virus