title: Novel Ranking System for Identifying Efficacious Anti-Influenza Virus PB2 Inhibitors.
abstract: Through antigenic drift and shifts, influenza virus infections continue to be an annual cause of morbidity in healthy populations and of death among elderly and at-risk patients. The emergence of highly pathogenic avian influenza viruses such as H5N1 and H7N9 and the rapid spread of the swine-origin H1N1 influenza virus in 2009 demonstrate the continued need for effective therapeutic agents for influenza. While several neuraminidase inhibitors have been developed for the treatment of influenza virus infections, these have shown a limited window for treatment initiation, and resistant variants have been noted in the population. In addition, an older class of antiviral drugs for influenza, the adamantanes, are no longer recommended for treatment due to widespread resistance. There remains a need for new influenza therapeutic agents with improved efficacy as well as an expanded window for the initiation of treatment. Azaindole compounds targeting the influenza A virus PB2 protein and demonstrating excellent in vitro and in vivo properties have been identified. To evaluate the in vivo efficacy of these PB2 inhibitors, we utilized a mouse influenza A virus infection model. In addition to traditional endpoints, i.e., death, morbidity, and body weight loss, we measured lung function using whole-body plethysmography, and we used these data to develop a composite efficacy score that takes compound exposure into account. This model allowed the rapid identification and ranking of molecules relative to each other and to oseltamivir. The ability to identify compounds with enhanced preclinical properties provides an opportunity to develop more-effective treatments for influenza in patients.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Vertex Pharmaceuticals Inc., Boston, Massachusetts, USA alice_tsai@vrtx.com.
authors.forename: Alice W
authors.initials: AW
authors.lastname: Tsai
authors.affiliation: Department of Infectious Diseases, Vertex Pharmaceuticals Inc., Boston, Massachusetts, USA.
authors.forename: Colleen F
authors.initials: CF
authors.lastname: McNeil
authors.affiliation: Department of Infectious Diseases, Vertex Pharmaceuticals Inc., Boston, Massachusetts, USA.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Leeman
authors.affiliation: Department of Infectious Diseases, Vertex Pharmaceuticals Inc., Boston, Massachusetts, USA.
authors.forename: Hamilton B
authors.initials: HB
authors.lastname: Bennett
authors.affiliation: Department of Materials Discovery and Characterization, Vertex Pharmaceuticals Inc., Boston, Massachusetts, USA.
authors.forename: Kwame
authors.initials: K
authors.lastname: Nti-Addae
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Vertex Pharmaceuticals Inc., Boston, Massachusetts, USA.
authors.forename: Cassey
authors.initials: C
authors.lastname: Huang
authors.affiliation: OnKognos Scientific Consulting and Services, Newton, Massachusetts, USA.
authors.forename: Ursula A
authors.initials: UA
authors.lastname: Germann
authors.affiliation: Department of Infectious Diseases, Vertex Pharmaceuticals Inc., Boston, Massachusetts, USA.
authors.forename: Randal A
authors.initials: RA
authors.lastname: Byrn
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Vertex Pharmaceuticals Inc., Boston, Massachusetts, USA.
authors.forename: Francoise
authors.initials: F
authors.lastname: Berlioz-Seux
authors.affiliation: Department of Infectious Diseases, Vertex Pharmaceuticals Inc., Boston, Massachusetts, USA.
authors.forename: Rene
authors.initials: R
authors.lastname: Rijnbrand
authors.affiliation: Department of Chemistry, Vertex Pharmaceuticals Inc., Boston, Massachusetts, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Clark
authors.affiliation: Department of Chemistry, Vertex Pharmaceuticals Inc., Boston, Massachusetts, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Charifson
authors.affiliation: Department of Infectious Diseases, Vertex Pharmaceuticals Inc., Boston, Massachusetts, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Jones
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001372:Aza Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral; D015870:Gene Expression; D007211:Indoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000821:virology; D053139:Oseltamivir / Q000494:pharmacology; D012107:Research Design; D012129:Respiratory Function Tests; D016019:Survival Analysis; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D001372:Aza Compounds; D007211:Indoles; C502893:PB2 protein, influenza virus; D014764:Viral Proteins; D053139:Oseltamivir