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）家族包含一些已知感染人类的最具传染性的病毒，如 麻疹（MeV）和腮腺炎（MuV）病毒，以及一些最致命的如亨德拉（HeV）和尼帕（NiV）病毒。 后者被列为世卫组织研发蓝图上的大流行病病原体， 致命的爆发时，从蝙蝠蔓延到人类和动物种群。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大流行威胁。支持 我们中心（AC/DC）的主要使命是开发口服直接作用的临床候选药物， 和新出现的流行性病毒威胁，项目3（P3）将测试、表征和优化主要的抗病毒攻击 AC/DC已经发现抗潜在大流行关注的副粘病毒（P3 CO）。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依赖的RNA聚合酶（RdRP）的机制不同的方式，并将确保 结构上不同的化学型对P3 CO的活性管道。EIDD-2749和GHP-88309是示例 口服生物可利用的NRPI和NNRPI化学型，对多个属的PMV有活性，具有广泛的生物学活性。 安全范围（SI>500），允许每日给药一次或两次的有利PK，并且具有非重叠和 适合度限制抗性谱。EIDD-2749还被证明对SARS-CoV-2（P1）和病毒有效 被P5和P6瞄准。这两种化合物抑制了将驱动重新迭代化学型的命中， 表型优化和先进的表征过程，这是P3的主要目标， 开发口服生物可利用的、结构多样的、广谱的抗PMV治疗剂， 值得正式IND开发的具有吸引力的特性。我们的假设是 PMV RdRP的保守结构和功能特征将允许开发口服有效的 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实现我们的目标并验证我们的假设： 核苷类似物作为亨尼帕病毒复制的临床相关抑制剂的参数（目的1）;我们将 开发靶向亨尼帕病毒复制复合物的非核苷RNA聚合酶抑制剂， 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 作为治疗药物候选物核苷类似物和非核苷RNA聚合酶抑制剂 麻疹病毒（aim 3）;我们将发现新的化学型，抑制不同的副粘病毒复制 (aim 4）。