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: 10544324
• 负责人: Richard K. Plemper
• 金额: $ 91.32万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544324
• 关键词: Academia; Address; Adult; Anabolism; Animal Model; Animals; Antiviral Agents; Antiviral Therapy; Avian Influenza A Virus; 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; Licensing; Medical; Medicine; 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; Respiratory Disease; Ribonucleosides; Risk; Seasons; Stains; 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; antiviral drug development; candidate selection; clinical candidate; clinical efficacy; clinically significant; design; drug discovery; efficacy evaluation; experience; human disease; improved; in vitro activity; in vivo; in vivo evaluation; influenza virus strain; influenzavirus; inhibitor; innovation; insight; mortality; mouse model; novel; novel therapeutics; pandemic disease; pandemic potential; pathogen; pathogenic virus; patient population; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical development; programs; prophylactic; pyrimidine analog; research clinical testing; respiratory virus; risk mitigation; 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).

概括 流感病毒是由于全世界呼吸道病毒感染引起的人类疾病的主要原因。是 这种合作伙伴关系的总体目标是推进新型嘧啶类模拟抗激素病毒类 朝着调查新的药品包装。该程序的设计是由我们的基础驱动的 假设有效的下一代治疗用于治疗流感的治疗必须是口服的， 显示针对人，禽和猪谱系的流感病毒分离株的广泛指示光谱，以及 涵盖流感A（IAV）和B（IBV）病毒。这些产品概况要求来自临床 由各种季节性流感病毒施加的负担，这是由 人畜共患病毒溢出到人口中，当前的FDA建议识别非 - 住院的成年人患有季节性流感作为初始临床测试的主要患者人群。 这些发育目标最好与直接表演治疗剂相满足，因为宿主针对宿主的抗病毒 疗法虽然通常在适应症范围内诱人范围广泛，但容易受到不可接受的副作用 与主要患者组不相容。 在长期的学术界/行业抗病毒伙伴关系的保护下，我们建立了双重 病原体药物筛查方案，允许同时自动鉴定靶病毒特异性 和广阔的候选人。在大规模的药物筛查运动中实施此测定 产生了具有亚微摩尔抗病毒效力的胞苷类似物。在该临床前的试点研究中 程序，我们已经证明，有效的抑制活性扩展到IAV和IBV分离株，涵盖病毒 代表人类和人畜共患谱系，包括高度致病的鸟类H5N1和H7N9病毒 主要的大流行威胁。铅化合物是口服生物利用物，有效地转换为活动 三磷酸在体内，并显示出持续的微摩尔肺组织浓度。我们已经演示了口头 小鼠对具有大流行潜力和 观察到在豚鼠传播模型中对病毒扩散的实质性抑制。准备 临床测试，该铅类别将经过机械表征和抗性分析（AIM 1）。 同时，将探索磷脂前药制剂，以提高严重的药物组织浓度 我们的屏幕中确定的疾病适应症和结构独立的替代方案将通过 化学铅开发以减轻发育失败的潜在风险（AIM 2）。 新兴磷脂前药的药代动力学和药效动力学特征将是 确定和体内耐受性（AIM 3）。临床候选者对季节性和 高度致病的病毒将在小鼠和雪貂中进行测试，先前药物暴露对发病机理的影响 检查了豚鼠评估的对病毒差的影响（AIM 4）。

项目成果

The impact of high-resolution structural data on stemming the COVID-19 pandemic.

• DOI: 10.1016/j.coviro.2021.05.005
• 发表时间: 2021-08
• 期刊: Current opinion in virology
• 影响因子: 5.9
• 作者: Cox RM;Plemper RK
• 通讯作者: Plemper RK

Quantitative efficacy paradigms of the influenza clinical drug candidate EIDD-2801 in the ferret model.

• DOI: 10.1016/j.trsl.2019.12.002
• 发表时间: 2020-04
• 期刊: Translational research : the journal of laboratory and clinical medicine
• 作者: Toots M;Yoon JJ;Hart M;Natchus MG;Painter GR;Plemper RK
• 通讯作者: Plemper RK

Progress and pitfalls of a year of drug repurposing screens against COVID-19.

• DOI: 10.1016/j.coviro.2021.06.004
• 发表时间: 2021-08
• 期刊: Current opinion in virology
• 影响因子: 5.9
• 作者: Sourimant J;Aggarwal M;Plemper RK
• 通讯作者: Plemper RK

Comparing molnupiravir and nirmatrelvir/ritonavir efficacy and the effects on SARS-CoV-2 transmission in animal models.

• DOI: 10.1038/s41467-023-40556-8
• 发表时间: 2023-08-07
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Cox, Robert M.;Lieber, Carolin M.;Wolf, Josef D.;Karimi, Amirhossein;Lieberman, Nicole A. P.;Sticher, Zachary M.;Roychoudhury, Pavitra;Andrews, Meghan K.;Krueger, Rebecca E.;Natchus, Michael G.;Painter, George R.;Kolykhalov, Alexander A.;Greninger, Alexander L.;Plemper, Richard K.
• 通讯作者: Plemper, Richard K.

Viral evolution identifies a regulatory interface between paramyxovirus polymerase complex and nucleocapsid that controls replication dynamics.

病毒进化确定了副粘病毒聚合酶复合物和控制复制动态的核衣壳之间的调节界面。

• DOI: 10.1126/sciadv.aaz1590
• 发表时间: 2020
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Sourimant,Julien;Thakkar,VidhiD;Cox,RobertM;Plemper,RichardK
• 通讯作者: Plemper,RichardK