Project 3 – Direct-Acting Antivirals against Paramyxoviruses

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，如 麻疹(MeV)和腮腺炎(Muv)病毒，以及一些最致命的病毒，如Hendra(HEV)和Nipah(Niv)病毒。 后者被列为世卫组织研发蓝图上的一种引起大流行关注的病原体，并已多次引起 当致命的疫情从蝙蝠蔓延到人类和动物种群时。蝙蝠是少校的主人 哺乳动物副粘病毒，包括埃尼帕病毒和其他新出现的大流行威胁。为了支持…… 我们中心(AC/DC)的主要任务是开发口服可用直接作用临床候选药物，以对抗现有的 和新出现的大流行病毒威胁，项目3(P3)将测试、表征和优化领先的抗病毒药物 AC/DC已经发现了针对可能引起大流行关注的副粘病毒(P3CO)的药物。我们的重点是 关于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)以不同的机械方式，并将确保 具有抗P3CO活性的结构多样化的化学类型的管道。EIDD-2749和GHP-88309是范例 NRPI和NNRPI化学类型是口服生物可用的，对多种PMV有效，具有广泛的 安全裕度(SI&gt；500)，允许每天给药一次或两次的有利PK，并具有无重叠和 适合度极限抗性图谱。EIDD-2749还被证明对SARS-CoV-2(P1)和病毒有效 以P5和P6为目标。这两种化合物例证了将驱动重新迭代的化合型转变为- P3的主要目标是表型优化和先进的表征过程，这是 开发口服生物利用型、结构多样化、广谱的抗PMV药物 药理上有吸引力的特性，保证了正式的IND开发。我们的驾驶假设是 PMV RdRP保守的结构和功能特征将允许开发口服有效性 直接作用的抗病毒药物。我们将利用AC/DC的集体专业知识和集成资源(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：我们将描述疗效 核苷类似物作为鸡痘病毒复制的临床相关抑制物的参数(目标1)；我们将 开发针对鸡痘病毒复制复合体的非核苷类RNA聚合酶抑制剂 或加强核苷类似物RNA聚合酶抑制剂治疗(目标2)；我们将评估这两种疗法的潜力 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药物 麻疹病毒(目标3)；我们将发现抑制副粘病毒分化复制的新化学类型 (目标4)。

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).