title: Inhibition of adenovirus replication by a trisubstituted piperazin-2-one derivative.
abstract: The number of disseminated adenovirus (Ad) infections continues to increase mostly due to the growing use of immunosuppressive treatments. Recipients of solid organ or hematopoietic stem cell transplants, mainly in pediatric units, exhibit a high morbidity and mortality due to these infections. Unfortunately, there are no Ad-specific antiviral drugs currently approved for medical use. To address this situation, we used high-throughput screening (HTS) of synthetic small molecule libraries to identify compounds that restrict Ad infection. Among the more than 25,000 compounds screened, we identified a hit compound that significantly inhibited Ad infection. The compound (15D8) is a trisubstituted piperazin-2-one derivative that showed substantial antiviral activity with little or no cytotoxicity at low micromolar concentrations. Compound 15D8 selectively inhibits Ad DNA replication in the nucleus, providing a potential candidate for the development of a new class of antiviral compounds to treat Ad infections.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 N. Torrey Pines Road, Mailcode IMM4, La Jolla, CA 92037, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Sanchez-Cespedes
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 N. Torrey Pines Road, Mailcode IMM4, La Jolla, CA 92037, USA.
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Moyer
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, Mailcode BCC483, La Jolla, CA 92037, USA.
authors.forename: Landon R
authors.initials: LR
authors.lastname: Whitby
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, Mailcode BCC483, La Jolla, CA 92037, USA.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 N. Torrey Pines Road, Mailcode IMM4, La Jolla, CA 92037, USA. Electronic address: gnemerow@scripps.edu.
authors.forename: Glen R
authors.initials: GR
authors.lastname: Nemerow
mesh_terms: D000256:Adenoviridae / Q000187:drug effects* / Q000502:physiology; D000998:Antiviral Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D010879:Piperazines / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D010879:Piperazines
keywords: Adenovirus; Antiviral compound; DNA replication inhibitor