Project 3 – Direct-Acting Antivirals against Paramyxoviruses

项目 3 — 针对副粘病毒的直接作用抗病毒药物

• 批准号: 10513944
• 负责人: Benhur Lee
• 金额: $ 539.3万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513944
• 关键词: 2019-nCoV; Acute Disease; Animal Model; Animals; Antiviral Agents; Automobile Driving; Callithrix; Chemicals; Chiroptera; Clinical Pharmacology; Complement; Complex; Data; Development; Disease; Disease Outbreaks; Docking; Dose; Drug Screening; Ensure; Epithelial Cells; Family; Family Picornaviridae; Ferrets; Fishes; Goals; Hamsters; Hendra Virus; Henipavirus; Home; Human; In Vitro; Individual; Intervention; Isoquinolines; Lead; Mammals; Measles; Measles virus; Mission; Modeling; Morbillivirus; Mumps; Nucleosides; Oral; Organoids; Paramyxovirus; Pathogenesis; Pharmacology; Phenotype; Population; Process; Property; Proteins; Quantitative Structure-Activity Relationship; RNA Polymerase Inhibitor; RNA Viruses; RNA-Directed RNA Polymerase; Resistance profile; Resource Allocation; Resources; Respirovirus; Route; Safety; Selection Criteria; Structure; System; Testing; Therapeutic; Tissues; Togaviridae; Triage; Vaccines; Vertebrates; Viral; Virus; base; cell type; clinical candidate; clinically relevant; counterscreen; drug candidate; efficacious treatment; fitness; in silico; in vivo; inhibitor; inhibitor therapy; macrophage; novel; nucleoside analog; pandemic disease; pathogen; pharmacophore; programs; prophylactic; research and development; respiratory; small molecule therapeutics; spillover event; transmission process; tripolyphosphate; viral RNA

The paramyxovirus (PMV) family contains some of the most contagious viruses known to infect humans such as measles (MeV) and mumps (MuV) virus, and some of the deadliest like Hendra (HeV) and Nipah (NiV) virus. The latter is listed on the WHO R&D blueprint as a pathogen of pandemic concern and has caused repeated deadly outbreaks when spilled over from bats into the human and animal populations. Bats are hosts to major mammalian paramyxoviruses, including the henipaviruses and other emerging pandemic threats. In support of our center’s (AC/DC) primary mission to develop orally available direct-acting clinical candidates against existing and emerging pandemic viral threats, Project 3 (P3) will test, characterize, and optimize the leading antiviral hits AC/DC has already discovered against paramyxoviruses of potential pandemic concern (P3CO). Our focus is on developing orally efficacious nucleoside analog and non-nucleoside RNA polymerase inhibitors. These target the conserved viral RNA-dependent RNA polymerase (RdRP) in mechanistically distinct ways and will ensure a pipeline of structurally diverse chemotypes active against P3CO. EIDD-2749 and GHP-88309 are exemplar NRPI and NNRPI chemotypes that are orally bioavailable, active against multiple genera of PMVs, have a wide safety margin (SI>500), favorable PK that allow for once or twice daily dosing, and have non-overlapping and fitness limiting resistance profiles. EIDD-2749 also has proven efficacy against SARS-CoV-2 (P1) and the viruses targeted by P5 and P6. These two compounds exemplify the hits that will drive the re-iterative chemotype-to- phenotype optimization and advanced characterization processes that underly the primary goal of P3, which is to develop orally bioavailable, structurally diverse, broad spectrum anti-PMV therapeutics with clinically and pharmacologically attractive properties that warrant formal IND development. Our driving hypothesis is that conserved structural and functional features of the PMV RdRP will allow for development of orally efficacious direct-acting antivirals. We will leverage the collective expertise and integrated resources of AC/DC (Cores A- F) to achieve our goal and test our hypothesis via the following four specific aims: we will characterize the efficacy parameters of nucleoside analogs as clinically relevant inhibitors of henipavirus replication (aim 1); we will develop non-nucleoside RNA polymerase inhibitors that target henipavirus replication complexes to complement or enhance nucleoside analog RNA polymerase inhibitor therapy (aim 2); we will evaluate the potential of both nucleoside analog and non-nucleoside RNA polymerase inhibitors as therapeutic drug candidates for morbilliviruses (aim 3); and we will discover new chemotypes that inhibit divergent paramyxovirus replication (aim 4).

Paramyxovirus（PMV）家族包含一些已知感染人类的​​最具传染性病毒，例如 麻疹（MEV）和腮腺炎病毒，以及一些最致命的亨德拉（Hev）和尼帕（NIV）病毒。 后来在WHO R＆D蓝图上列出了大流行病的病原体，并引起了重复 当从蝙蝠洒到人类和动物种群中时，致命爆发。蝙蝠是主人 哺乳动物的丙糖病毒，包括HENIPAVIRES和其他新兴的大流行威胁。支持 我们中心（AC/DC）的主要任务，是针对现有的口服直接作用临床候选者 和新兴的大流行病毒威胁，项目3（P3）将测试，表征和优化领先的抗病毒命中率 AC/DC已经发现了针对潜在大流行关注（P3CO）的帕克诺病毒。我们的重点是 开发口服有效的核苷类似物和非核苷RNA聚合酶抑制剂。这些目标 以机械方式不同的方式，配置的病毒RNA依赖性RNA聚合酶（RDRP），将确保 针对P3CO活性的结构上不同的化学型的管道。 EIDD-2749和GHP-88309是典范 口服生物利用的NRPI和NNRPI化学型，具有多个PMV属的活性 安全利润率（SI> 500），有利的PK，可以每天或两次给药，并具有不重叠 适应性限制电阻曲线。 EIDD-2749还针对SARS-COV-2（P1）和病毒具有公认的有效性 由P5和P6靶向。这两种化合物典范的效果将驱动重新介绍化学型至上 表型优化和高级表征过程，这些过程是P3的主要目标，即 通过临床和 具有正式开发的药理具有吸引力的特性。我们的驾驶假设是 PMV RDRP的保守结构和功能特征将允许开发口服高效 直接作用抗病毒药。我们将利用AC/DC的集体专业知识和集成资源（核心A- f）实现我们的目标并通过以下四个特定目的来检验我们的假设：我们将表征效率 核苷类似物的参数是HENIPAVIRUS复制的临床相关抑制剂（AIM 1）；我们将 开发靶向HENIPAVIRUS复制复合物以完成的非核苷RNA聚合酶抑制剂 或增强核外侧类似RNA聚合酶抑制剂疗法（AIM 2）；我们将评估两者的潜力 核苷类似物和非核苷RNA聚合酶抑制剂作为治疗药物的候选者 病毒病毒（AIM 3）；我们将发现新的化学型，可抑制发散的帕托马病毒复制 （目标4）。