Development of Benzodiazepine YFV NS4B inhibitors as therapeutic agents for Yellow Fever

开发苯二氮卓 YFV NS4B 抑制剂作为黄热病治疗剂

基本信息

批准号：
10395505
负责人：
Jinhong Chang
金额：
$ 68.08万
依托单位：
BARUCH S. BLUMBERG INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10395505
关键词：
Acetic Acids Acute Africa Alanine Amino Acids Animals Antiviral Agents Area Attenuated Benzodiazepines Binding Binding Proteins Biological Biological Availability Body Weight decreased Cells Central America Cessation of life Chemicals Clinical Complex Consequentialism Dengue Infection Development Dimerization Disease Disease Outbreaks Drug Kinetics Excretory function Goals Hamsters Hemorrhage Impairment In Vitro Innate Immune Response Insecta Interferons Knowledge Latin America Lead Libraries Mammalian Cell Maximum Tolerated Dose Medical Membrane Metabolism Modification Molecular Mus Natural Immunity Nonstructural Protein Oral Oral Administration Patients Periodicals Persons Plasma Proteins Proline Proteins RNA replication Research Risk Role Safety Serine Signal Transduction Pathway Solubility South America Therapeutic Therapeutic Agents Threonine TimeLine Toxicology Translating Treatment Efficacy Treatment Protocols Vaccination Viral Viral Load result Viral Physiology Virus Activation Virus Diseases Virus Replication Yellow Fever Yellow Fever Vaccine Yellow Fever Virus Infection Yellow fever virus absorption anti-viral efficacy clinical candidate clinical development cytokine cytotoxicity fitness high throughput screening improved in vivo inhibitor lead optimization liver injury mortality novel pre-clinical preclinical development preclinical study prevent protein metabolism rational design receptor response scale up viral RNA viral resistance

项目摘要

ABSTRACT This is a proposal to develop a highly selective and potent antiviral benzodiazepine compound against yellow fever virus (YFV) as a therapeutic agent for treatment of yellow fever and understand its antiviral mechanism. Yellow fever is an acute viral hemorrhagic disease which threatens approximately one billion people living in tropical areas of Africa, Central and South America. Although a highly effective yellow fever vaccine has been available for more than seven decades, the low vaccination rate fails to prevent outbreaks in at-risk regions. It has been estimated that up to 1.7 million YFV infections occur in Africa each year, resulting in 29,000 to 60,000 deaths, which outnumber the estimated death toll of global dengue virus infection. Thus far, there is no specific antiviral treatment for yellow fever. To cope with this medical challenge, we discovered an acetic acid benzodiazepine (BDAA) compound that potently inhibited YFV replication in both mammalian and insect cells by targeting the viral non-structural 4B (NS4B) protein. We have already demonstrated in YFV-infected hamsters that oral administration of BDAA significantly protected the animals from death, reduced viral load by greater than 2 logs and attenuated viral infection-induced liver injury and body weight loss. Building on these encouraging preclinical studies, we propose in this project to optimize the lead compound to obtain benzodiazepine derivatives with improved solubility and reduced plasma protein binding ability to achieve improved in vivo antiviral efficacy and safety profile. Meanwhile, we will continue our efforts toward understanding the molecular mechanism by which BDAA and its derivatives inhibit YFV replication. Specifically, impacts of the compound on NS4B protein metabolism, integrity and function of viral RNA replication complex as well as YFV interaction with host cellular innate immune response will be investigated. At the completion of this project, we will nominate an optimized benzodiazepine derivative as well as backup compounds for further preclinical/clinical development. In addition to knowing how the compound inhibits YFV replication, our studies proposed in this project should also enrich our knowledge on the function of NS4B protein in YFV replication and evasion of host innate immunity.

抽象的这是一项提议，旨在开发高度选择性和有效的抗病毒苯二氮卓类化合物对黄色发烧病毒（YFV）是一种治疗黄热病并了解其抗病毒药机制的治疗剂。黄热病是一种急性病毒出血性疾病，威胁着大约十亿人非洲，中美洲和南美的热带地区。尽管高效的黄热疫苗已经七十多年来可用的疫苗接种率无法防止处于危险区域的爆发。它据估计，每年在非洲发生多达170万种YFV感染，导致29,000 60,000人死亡，超过了全球登革热病毒感染的估计死亡人数。到目前为止，没有特异性抗病毒治疗黄热病。为了应对这一医疗挑战，我们发现了乙酸苯二氮卓（BDAA）复合于哺乳动物和昆虫细胞中有效抑制YFV复制的复合通过靶向病毒非结构性4B（NS4B）蛋白。我们已经在YFV感染的口服BDAA的仓鼠显着保护动物免受死亡的影响，通过大于2个原木和病毒感染引起的肝损伤和体重减轻。建立在这些基础上令人鼓舞的临床前研究，我们在该项目中建议优化铅化合物以获得具有提高溶解度和血浆蛋白结合能力的苯二氮卓类衍生物的实现能力改善了体内抗病毒功效和安全性。同时，我们将继续努力了解BDAA及其衍生物抑制YFV复制的分子机制。具体而言，该化合物对NS4B蛋白质代谢，病毒RNA的完整性和功能的影响将研究复制复合物以及与宿主细胞先天免疫反应的YFV相互作用。该项目完成时，我们将提名优化的苯二氮卓类衍生物和备份用于进一步的临床前/临床发育的化合物。除了知道化合物如何抑制YFV之外复制，我们在该项目中提出的研究也应丰富我们对NS4B功能的知识 YFV复制和逃避宿主先天免疫的蛋白质。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A yellow fever virus NS4B inhibitor not only suppresses viral replication, but also enhances the virus activation of RIG-I-like receptor-mediated innate immune response.

DOI：
10.1371/journal.ppat.1010271
发表时间：
2022-01
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Gao Z;Zhang X;Zhang L;Wu S;Ma J;Wang F;Zhou Y;Dai X;Bullitt E;Du Y;Guo JT;Chang J
通讯作者：
Chang J

Interferon Control of Human Coronavirus Infection and Viral Evasion: Mechanistic Insights and Implications for Antiviral Drug and Vaccine Development.