Development of Antivirals against Filovirus Replication

抗丝状病毒复制的抗病毒药物的开发

• 批准号: 10513686
• 负责人: Ralph S Baric
• 金额: $ 379.6万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 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/10513686
• 关键词: Africa; African; Amino Acid Sequence; Animal Model; Binding; Biological Assay; Bundibugyo virus; Case Fatality Rates; Cells; Cessation of life; Chemicals; Chemistry; Clinical Trials; Collaborations; Coupled; Crowding; DNA; Data; Democratic Republic of the Congo; Development; Digit structure; Disease Outbreaks; Disseminated Intravascular Coagulation; Docking; Dose; Drug Kinetics; Ebola; Ebola virus; Enzymatic Biochemistry; Enzymes; Evaluation; Excretory function; Exhibits; Ferrets; Filoviridae Infections; Filovirus; Formulation; Goals; Hepatocyte; Human; Immune response; In Vitro; Infection; Lead; Libraries; Liver; Marburgvirus; Metabolism; Methods; Modeling; Molecular Virology; Multiple Organ Failure; Nucleosides; Oral; Organ; Pharmaceutical Preparations; Polymerase; Positioning Attribute; Process; Property; Proteins; RNA-Directed RNA Polymerase; Reporter; Research Contracts; Research Personnel; Risk; Rodent Model; Roentgen Rays; Safety; Series; Site; Structure-Activity Relationship; Sudan Ebola virus; System; Testing; Therapeutic; Toxic effect; Vaccines; Validation; Viral; Viral Load result; Viral Proteins; Virus; absorption; analog; anti-viral efficacy; antiviral drug development; base; cell type; drug development; drug discovery; druggable target; efficacy study; experience; human disease; improved; in vivo; industry partner; innovation; lead optimization; macrophage; new therapeutic target; novel; nucleoside analog; pre-clinical; programs; reverse genetics; screening; small molecule; success; virtual

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.

概要（项目3：Kawaoka） 作为快速新兴抗病毒药物开发倡议-AViDD中心（READDI-AC）计划的一部分， 项目3：丝状病毒的目标是鉴定和开发具有强大抗病毒活性的有前景的命中和先导化合物。 丝状病毒活性，同时也通过鉴定新的丝状病毒，推进丝状病毒药物开发领域。 化学实体和可药用目标。在目标1（“鉴定复合命中物和保守丝状病毒 药物靶点“），将采用多管齐下的方法，通过使用不同的 筛选测定包括靶向核苷文库、DNA编码的文库筛选、基于酶的 筛选，以及其他项目中有前途的化合物。我们还将确定和验证可用药的目标网站 在丝状病毒聚合酶（L）蛋白的功能结构域中， 可适用于发现另外的广泛活性的抗丝状病毒小分子化合物， 发现核心B。在目标2中，Adman Core A和MedChem Core D对命中后化合物进行优先排序 （“针对丝状病毒的命中化合物的优化”）将确定2-4个命中系列用于命中-探针优化 MedChem Core D.该核心将合成用于抗病毒评价的化合物类似物，改进其抗病毒活性。 通过构效关系研究活性，并确定其药物吸收、分布、代谢， 排泄和药代动力学（PK）特性。除了目标1中确定的目标化合物外，我们还将 在这个项目中，通过与Seley-Radtke博士合作， 合作调查员将评价化合物和合成的类似物的抗病毒活性， 在Enzymology Core C进行的基于酶的测定和使用新型埃博拉报告基因的基于细胞的测定中， 病毒系统和真实的Filoviruses项目3.两种先导化合物将进入目标3（“先导 开发以确定体内疗效“），其中将进行研究以产生临床前 包.通过MedChem核心D、制剂和体内PK研究的输入，更好地了解 将进行化合物的PK特性，以推进体内抗病毒功效研究 由签约的研究机构提供。抗病毒疗效研究将由项目3进行，首先在啮齿动物中进行 丝状病毒感染模型，然后在雪貂模型中进行确证性研究。最终，我们希望 目标，命中，线索和化学探针，用于公众人群共享，以及一种化合物的IND前启用数据 对至少三种重要的埃博拉病毒（可能还有马尔堡病毒）具有抗病毒活性，达到 早期体内优化，目的是吸引行业合作伙伴最终将药物推向临床 审判