title: Targeting Influenza A Virus RNA Promoter.
abstract: The emergence of drug-resistant strains of influenza virus makes exploring new classes of inhibitors that target universally conserved viral targets a highly important goal. The influenza A viral genome is made up of eight single-stranded RNA-negative segments. The RNA promoter, consisting of the conserved sequences at the 3' and 5' end of each RNA genomic segment, is universally conserved among influenza A virus strains and in all segments. Previously, we reported on the identification and NMR structure of DPQ (6,7-dimethoxy-2-(1-piperazinyl)-4-quinazolinamine) (compound 1) in complex with the RNA promoter. Here, we report on additional screening and SAR studies with compound 1, including ex vivo anti-influenza activity assays, resulted in improved cellular activity against influenza A virus in the micromolar range.
authors: Infectious and Inflammatory Disease Center and Cancer Center, Sanford Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.|Sanford Burnham Graduate School of Biomedical Sciences, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors: Angel
authors: A
authors: Bottini
authors: Infectious and Inflammatory Disease Center and Cancer Center, Sanford Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors: Surya K
authors: SK
authors: De
authors: Infectious and Inflammatory Disease Center and Cancer Center, Sanford Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors: Bainan
authors: B
authors: Wu
authors: Department of Chemistry, University of Washington, Seattle, WA, 98195-1700, USA.
authors: Changyan
authors: C
authors: Tang
authors: Department of Chemistry, University of Washington, Seattle, WA, 98195-1700, USA.
authors: Gabriele
authors: G
authors: Varani
authors: Infectious and Inflammatory Disease Center and Cancer Center, Sanford Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors: Maurizio
authors: M
authors: Pellecchia
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D009980:Influenza A virus / Q000187:drug effects / Q000235:genetics*; D061985:Madin Darby Canine Kidney Cells / Q000187:drug effects / Q000821:virology; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D019151:Peptide Library; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D012367:RNA, Viral / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: C000590131:6,7-dimethoxy-2-(1-piperazinyl)-4-quinazolinamine; D000998:Antiviral Agents; D019151:Peptide Library; D010879:Piperazines; D011799:Quinazolines; D012367:RNA, Viral
keywords: chemical biology; drug design; drug discovery