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

Michael O Clarke; Richard Mackman; Daniel Byun; Hon Hui; Ona Barauskas; Gabriel Birkus; Byoung-Kwon Chun; Edward Doerffler; Joy Feng; Kapil Karki; Gary Lee; Michel Perron; Dustin Siegel; Swami Swaminathan; William Lee

doi:10.1016/j.bmcl.2015.04.073

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

Bioorg Med Chem Lett. 2015 Jun 15;25(12):2484-7. doi: 10.1016/j.bmcl.2015.04.073. Epub 2015 Apr 29.

Authors

Affiliations

¹ Gilead Sciences, Inc., Foster City, CA 94404, United States.
² Gilead Sciences, Inc., Foster City, CA 94404, United States. Electronic address: rmackman@gilead.com.

PMID: 25978965
DOI: 10.1016/j.bmcl.2015.04.073

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.

Keywords: DNA polymerase γ; Mitochondria; Mitochondrial RNA polymerase; Nucleoside; Respiratory syncytial virus.

MeSH terms

Adenosine / chemical synthesis
Adenosine / chemistry*
Adenosine / pharmacology
Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry*
Antiviral Agents / pharmacology
Aza Compounds / chemistry
DNA-Directed DNA Polymerase / chemistry*
DNA-Directed DNA Polymerase / metabolism
Drug Evaluation, Preclinical
Nucleic Acid Synthesis Inhibitors / chemical synthesis
Nucleic Acid Synthesis Inhibitors / chemistry*
Nucleic Acid Synthesis Inhibitors / pharmacology
RNA / chemistry*
RNA / metabolism
RNA, Mitochondrial
RNA-Dependent RNA Polymerase / antagonists & inhibitors*
RNA-Dependent RNA Polymerase / metabolism
Respiratory Syncytial Viruses / drug effects
Respiratory Syncytial Viruses / enzymology*
Respiratory Syncytial Viruses / physiology*
Structure-Activity Relationship
Virus Replication / drug effects

Substances

Antiviral Agents
Aza Compounds
Nucleic Acid Synthesis Inhibitors
RNA, Mitochondrial
RNA
RNA-Dependent RNA Polymerase
DNA-Directed DNA Polymerase
Adenosine