Development of Antivirals against Filovirus Replication

总结(项目3：川冈) 作为迅速兴起的抗病毒药物开发倡议-AViDD中心(READDI-AC)计划的一部分， 项目3：丝状病毒的目标是识别和开发具有强大抗病毒能力的有前景的命中和前导化合物。 丝状病毒的活性，同时也通过鉴定新的丝状病毒来推进丝病毒药物的开发 化学实体和可下药目标。目标1(‘鉴定复合HITS和保守的丝状病毒 可药物靶点‘)，将使用多管齐下的方法通过使用不同的 筛选分析包括靶向核苷文库、DNA编码文库筛选、基于酶的 筛选，以及来自其他项目的有希望的化合物。我们还将识别和验证可用药的目标站点 通过AlphaFold和片段作图，在丝状病毒聚合酶(L)蛋白的功能域中， 可能适用于发现新的广谱抗丝病毒小分子化合物 发现核心B。在目标2中，Adman核心A和MedChem核心D对命中化合物进行了优先排序 (‘针对丝状病毒的命中化合物的优化’)将确定2-4个命中系列以进行命中到探针的优化 该核心将合成用于抗病毒评估的化合物类似物，改进其 通过构效关系研究，确定它们的药物吸收、分布、代谢 排泄和药代动力学(PK)特性。除了目标1中确定的热门化合物外，我们还将带来 在这个项目中，两个核苷类似物通过与Seley-Radtke博士的合作对抗丝状病毒， 一名合作调查员。化合物和合成的类似物的抗病毒活性将被评估为抗病毒。 酶学核心C的酶分析和使用新的埃博拉报告的细胞分析的广度- 病毒系统和真正的丝状病毒由项目3。两个先导化合物将进入目标3(‘铅 开发以建立体内疗效‘)，其中将进行研究，以产生临床前 包裹。来自MedChem Core D、配方和体内PK研究的投入，以获得更好的理解 将对化合物的PK特性进行体内抗病毒疗效研究 由签约的研究机构负责。抗病毒效果研究将由项目3进行，首先是在啮齿动物身上 丝状病毒感染模型，随后在雪貂模型中进行验证性研究。最终，我们希望能够交付 用于公共人群共享的目标、命中、线索和化学探测器，以及一种化合物的预IND启用数据 对至少三种重要的埃博拉病毒具有抗病毒活性，可能还有马尔堡病毒，达到 早期体内优化，目标是吸引行业合作伙伴(S)最终将药物转移到临床 审判。

SUMMARY (Project 3: Kawaoka) As part of the Rapidly Emerging Antiviral Drug Development Initiative-AViDD Center (READDI-AC) program, the goal of Project 3: Filoviruses is to identify and develop promising hit and lead compounds with robust anti- filovirus activity, while also advancing the field of filovirus drug development through the identification of new chemical entities and druggable targets. In Aim 1 (‘Identification of compound hits and conserved filovirus druggable target sites’), a multipronged approach will be used to identify hit compounds by using different screening assays including targeted nucleoside libraries, a DNA-encoded library screen, enzyme-based screens, and promising compounds from other Projects. We will also identify and validate druggable target sites in the functional domains of the filovirus polymerase (L) protein by using AlphaFold and fragment mapping, which may be applicable to the discovery of additional broadly active anti-filovirus small molecule compounds by Discovery Core B. After hit compounds are prioritized by Adman Core A and MedChem Core D, in Aim 2 (‘Optimization of hit compounds against filoviruses’) 2–4 hit series will be identified for Hit-to-Probe optimization by MedChem Core D. This core will synthesize compound analogs for antiviral evaluation, improve upon their activity via structural-activity relationship studies, and determine their drug absorption, distribution, metabolism, excretion and pharmacokinetic (PK) properties. In addition to hit compounds identified in Aim 1, we will bring into this program, two hit nucleoside analogs against filoviruses through a collaboration with Dr. Seley-Radtke, a co-investigator. The antiviral activity of the compounds and synthesized analogs will be evaluated for antiviral breadth in enzyme-based assays by Enzymology Core C and in cell-based assays using a novel Ebola reporter- virus system and authentic filoviruses by Project 3. Two lead compounds will advance into Aim 3 (‘Lead development to establish in vivo efficacy’), where the studies will be carried out to generate a pre-clinical package. With input from MedChem Core D, formulation and in vivo PK studies to gain a better understanding of the PK properties of the compounds for their advancement to in vivo antiviral efficacy studies will be carried out by contracted research organizations. Antiviral efficacy studies will be carried out by Project 3, first in rodent models of filovirus infection, followed by confirmatory studies in a ferret model. Ultimately, we expect to deliver targets, hits, leads, and chemical probes for public crowd-sharing, and pre-IND enabling data for one compound with antiviral activity against at least three important Ebola viruses, and possibly Marburg virus, to the stage of early in vivo optimization with the goal of attracting an industry partner(s) to eventually move the drug to clinical trials.