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).

副粘病毒 (PMV) 家族包含一些已知可感染人类的​​最具传染性的病毒，例如 麻疹 (MeV) 和腮腺炎 (MuV) 病毒，以及一些最致命的病毒，如亨德拉 (HeV) 和尼帕 (NiV) 病毒。 后者被世界卫生组织研发蓝图列为大流行病病原体，并已引起反复 当从蝙蝠传播到人类和动物种群时，就会爆发致命的疫情。蝙蝠是主要的宿主 哺乳动物副粘病毒，包括亨尼帕病毒和其他新出现的流行病威胁。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药物 和新出现的流行性病毒威胁，项目 3 (P3) 将测试、表征和优化领先的抗病毒药物 AC/DC 已经发现了针对潜在大流行问题的副粘病毒 (P3CO)。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 保守的病毒RNA依赖性RNA聚合酶（RdRP）以机械上不同的方式，并将确保 具有抗 P3CO 活性的结构多样的化学型的管道。 EIDD-2749 和 GHP-88309 是示例 NRPI 和 NNRPI 化学型可口服生物利用，对多种 PMV 属具有活性，具有广泛的用途 安全裕度（SI>500），有利的 PK，允许每天给药一次或两次，并且具有非重叠和 健身限制阻力曲线。 EIDD-2749 还被证明对 SARS-CoV-2 (P1) 和病毒有效 P5和P6的目标。这两种化合物例证了将驱动重复化学型到-的命中 表型优化和高级表征过程是 P3 的主要目标，即 开发口服生物可利用的、结构多样的、广谱的抗 PMV 治疗药物，并进行临床和 药理学上有吸引力的特性值得正式的 IND 开发。我们的驾驶假设是 PMV RdRP 的保守结构和功能特征将有助于开发口服有效的药物 直接作用的抗病毒药物。我们将利用 AC/DC（核心 A- F）通过以下四个具体目标来实现我们的目标并检验我们的假设：我们将描述功效 作为亨尼帕病毒复制的临床相关抑制剂的核苷类似物的参数（目标 1）；我们将 开发针对亨尼帕病毒复制复合物的非核苷 RNA 聚合酶抑制剂以补充 或增强核苷类似物RNA聚合酶抑制剂治疗（目标2）；我们将评估两者的潜力 核苷类似物和非核苷RNA聚合酶抑制剂作为候选治疗药物 麻疹病毒（目标 3）；我们将发现抑制不同副粘病毒复制的新化学型 （目标 4）。