Development of a Broad-Spectrum Inhibitor against Seasonal and Highly-Pathogenic Influenza Viruses

针对季节性和高致病性流感病毒的广谱抑制剂的开发

• 批准号: 10080034
• 负责人: Richard K. Plemper
• 金额: $ 97.96万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-08 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10080034
• 关键词: Academia; Address; Adult; Anabolism; Animal Model; Animals; Antiviral Agents; Antiviral Therapy; Avian Influenza A Virus; Back; Bioavailable; Biological Assay; Biological Availability; Birds; Canis familiaris; Cavia; Cells; Cessation of life; Chemicals; Clinic; Clinical; Complex; Cytidine; Development; Disease; Disease Management; Drug Exposure; Drug Kinetics; Drug Screening; Elderly; Eligibility Determination; Esters; Failure; Family suidae; Ferrets; Formulation; Frequencies; Generations; Human; Industry; Infection; Influenza; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H7N9 Subtype; Influenza A virus; Influenza B Virus; Investigational Drugs; Joints; Lead; Lung diseases; Medical; Modeling; Molecular; Mus; Oral; Oseltamivir; Pathogenesis; Pathogenicity; Patients; Pattern; Pharmaceutical Preparations; Pharmacodynamics; Phospholipids; Pilot Projects; Polymerase; Population; Preparation; Prodrugs; Productivity; Program Development; Protocols documentation; Recombinants; Recommendation; Reporter; Resistance; Resistance profile; Ribonucleosides; Risk; Seasons; Stains; Structure; Structure of parenchyma of lung; Structure-Activity Relationship; Testing; Therapeutic; Tissues; Toxicology; Treatment Efficacy; United States; Vaccinated; Vaccines; Viral; Viral Respiratory Tract Infection; Virus; Virus Diseases; Virus Inhibitors; Work; Zoonoses; analog; anti-influenza; base; clinical candidate; clinical efficacy; clinically significant; design; drug development; drug discovery; experience; human disease; improved; in vitro activity; in vivo; in vivo evaluation; influenza virus strain; influenzavirus; inhibitor/antagonist; innovation; insight; mortality; mouse model; novel; novel therapeutics; pandemic disease; pandemic influenza; pathogen; pathogenic virus; patient population; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical development; programs; prophylactic; pyrimidine analog; research clinical testing; respiratory virus; scaffold; seasonal influenza; side effect; small molecule; standard of care; synergism; therapeutic candidate; transcriptome sequencing; transmission process; tripolyphosphate; viral resistance; zoonotic spillover

Summary Influenza viruses are the leading cause of human disease due to respiratory viral infection worldwide. It is the overarching objective of this partnership to advance a novel pyrimidine analog anti-influenza virus class towards an investigational new drug-enabling package. The design of this program is driven by our underlying hypothesis that effective next-generation therapeutics for the treatment of influenza must be orally available, display a broad indication spectrum against influenza virus isolates of human, avian, and swine lineages, and covers both influenza A (IAV) and B (IBV) viruses. These product profile demands are derived from the clinical burden imposed by the diverse spectrum of seasonal influenza viruses, the pandemic potential arising from spillover of zoonotic viruses into the human population, and current FDA recommendations that recognize non- hospitalized adults suffering from seasonal influenza as the primary patient population for initial clinical testing. These developmental objectives are best met with direct acting therapeutics, since host-targeted antiviral therapies, although often tantalizingly broad in indication range, are prone to unacceptable side effects that are incompatible with the primary patient group pursued. Under the umbrella of a long-term academia/industry antiviral partnership, we have established a dual- pathogen drug screening protocol that allows the simultaneous automated identification of target virus-specific and broad-spectrum candidates. Implementation of this assay in a large-scale drug screening campaign has yielded a cytidine analog with sub-micromolar antiviral potency. In pilot studies underpinning this preclinical program, we have demonstrated that potent inhibitory activity extends to IAV and IBV isolates, covers viruses representing human and zoonotic lineages, and includes highly pathogenic avian H5N1 and H7N9 viruses of major pandemic threat. The lead compound is orally bioavailable, efficiently converted to the active triphosphate in vivo, and showed sustained micromolar lung tissue concentrations. We have demonstrated oral efficacy in mice against seasonal and highly pathogenic avian influenza viruses with pandemic potential and observed substantial suppression of viral spread in the guinea pig IAV transmission model. In preparation of clinical testing, this lead class will be subjected to mechanistic characterization and resistance profiling (aim 1). In parallel, phospholipid prodrug formulations will be explored to boost drug tissue concentrations for severe disease indications and a structurally independent alternative identified in our screen will be advanced through chemical lead development for back-up to alleviate the potential risk of developmental failure (aim 2). Pharmacokinetic and pharmacodynamic profiles of emerging phospholipid prodrug and back-up leads will be generated and in vivo tolerability determined (aim 3). Efficacy of clinical candidates against seasonal and highly-pathogenic viruses will be tested in mice and ferrets, the effect of prior drug exposure on pathogenesis examined, and the impact on viral spreads assessed in guinea pigs (aim 4).

总结