Development of Antivirals against Filovirus Replication

抗丝状病毒复制的抗病毒药物的开发

基本信息

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
项目类别：
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

项目摘要

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.

摘要（项目 3：川冈）作为快速新兴抗病毒药物开发计划 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作用的有前景的命中化合物和先导化合物。丝状病毒活性，同时还通过鉴定新的丝状病毒药物开发领域目标 1（“化合物命中和保守丝状病毒的鉴定”）可成药的靶位点”），将采用多管齐下的方法，通过使用不同的方法来识别命中化合物筛选分析包括靶向核苷文库、DNA 编码文库筛选、酶基筛选我们还将识别和验证可成药的靶位点。通过使用 AlphaFold 和片段图谱分析丝状病毒聚合酶 (L) 蛋白的功能域，可能适用于发现其他具有广泛活性的抗丝状病毒小分子化合物 Discovery Core B. 在目标 2 中，Adman Core A 和 MedChem Core D 优先考虑命中后的化合物（“针对丝状病毒的命中化合物的优化”）将确定 2-4 个命中序列以用于命中探针优化由 MedChem Core D 开发。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，确定其药物吸收、分布、代谢、除了目标 1 中已确定的化合物外，我们还将带来排泄和药代动力学 (PK) 特性。通过与 Seley-Radtke 博士合作，在该计划中引入了两种针对丝状病毒的核苷类似物，共同研究者将评估化合物和合成类似物的抗病毒活性。 Enzymology Core C 进行基于酶的检测以及使用新型埃博拉报告基因进行基于细胞的检测的广度项目 3 的病毒系统和真实的丝状病毒。两种先导化合物将进入目标 3（“先导化合物”）开发以确定体内功效”），其中将进行研究以产生临床前借助 MedChem Core D、配方和体内 PK 研究的输入，以获得更好的理解。将进行化合物的 PK 特性研究，以促进其进入体内抗病毒功效研究抗病毒功效研究将由项目 3 进行，首先是在啮齿类动物中进行。我们希望最终能够实现丝状病毒感染模型，然后在雪貂模型中进行验证性研究。用于公众共享的目标、命中、先导化合物和化学探针，以及一种化合物的 IND 前支持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试验。