Novel filovirus entry inhibitors based on a pseudo-symmetrical biphenyl core

基于伪对称联苯核心的新型丝状病毒进入抑制剂

基本信息

批准号：
8904017
负责人：
Lijun Rong
金额：
$ 28.86万
依托单位：
MICROBIOTIX, INC
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8904017
关键词：
Address Affinity Animal Model Antiviral Agents Antiviral Therapy Biological Assay CCR5 gene Categories Cell membrane Cells Centers for Disease Control and Prevention (U.S.)Clinical Development Disease Outbreaks Dose Drug Kinetics Ebola virus Exhibits Family Filoviridae Filovirus Frankfurt-Marburg Syndrome Virus G Protein-Coupled Receptor Genes Glycoproteins HIV HIV Entry Inhibitors HIV Envelope Protein gp120 Human Immune response In Vitro Infection Inhibitory Concentration 50 Lead Libraries Liver Microsomes Mediating Medical Membrane Fusion Metabolic Modification National Institute of Allergy and Infectious Disease Nature Oral Pathogenesis Pathway interactions Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phase Primates Property Protein Isoforms Protocols documentation Reporter Research SB224289 Safety Screening Result Series Structure Structure-Activity Relationship T-20 Therapeutic Time TimeLine Tissues Toxic effect Tropism United States National Institutes of Health Vaccination Vaccine Therapy Vaccines Viral Viral Hemorrhagic Fevers Virus Virus Diseases Virus Inhibitors Western Africa analog base biodefense cytotoxicity design diphenyl improved indexing inhibitor/antagonist meetings member mortality nonhuman primate novel pre-clinical public health relevance receptor binding scaffold small molecule small molecule libraries stem therapeutic target tissue culture vaccine candidate

项目摘要

DESCRIPTION (provided by applicant): Ebola (EBOV) and Marburg (MARV) viruses belong to the family Filoviridae and can cause fatal hemorrhagic fevers characterized by widespread tissue destruction with an incubation period of 4-14 days. Because of the safety concerns, these viruses are designated as biosafety level 4 agents. Currently there is no effective vaccine or therapeutic treatment against filoviral infection and pathogenesis in humans. Although several promising vaccine candidates have been shown to be effective in eliciting host immune responses and to protect primates against viral infection, the minimal time required for vaccination (at least one month) and the sporadic nature of outbreaks reinforce the urgent need to develop potent, small molecule inhibitors against filoviral infections. Thus it is imperative to identify and develop potent inhibitors against filoviral infection. These inhibitors are considered to be of paramount importance for use during filoviral outbreaks or bioterrorist attacks. This application defines a plan to develop potent small molecule inhibitors, which block entry of EBOV and MARV into host cells. Entry of EBOV and MARV is mediated by a single viral glycoprotein (GP), which is considered one of the major therapeutic targets. GP consists of two subunits, GP1 and GP2; GP1 is responsible for receptor binding and host tropism, while GP2 mediates viral/cell membrane fusion and viral entry. We have used an HTS protocol targeting GP-mediated viral entry to screen a small molecule library, and we have identified compounds that inhibit entry of infectious EBOV/MARV (IC50 values =25 µM). These hit compounds exhibit selectivity for EBOV/MARV entry. The overall objective of this Phase I application is to develop these inhibitors as potential anti-filoviral therapeutics. This application will focus on the folloing three specific aims: (1) Synthesize structurally diverse analogs of the anti-Ebola SB699551 hit series based on structure-activity relationships (SARs) to improve potency and selectivity. (2) Validate the lead inhibitor candidates in the infectious assay and investigate the mechanism of action (MOA) of the EBOV/MARV inhibitors. (3) Select EBOV/MARV inhibitors with in vitro ADME properties suitable for i.v. and oral dosing.

描述（申请人提供）：埃博拉病毒（EBOV）和马尔堡病毒（MARV）属于丝状病毒科，可引起致命的出血热，其特征是广泛的组织破坏，潜伏期为 4-14 天。出于安全考虑，这些病毒。尽管几种有希望的候选疫苗已被证明是有效的，但目前还没有针对人类丝状病毒感染和发病机制的有效疫苗或治疗方法。在引发宿主免疫反应并保护灵长类动物免受病毒感染方面，疫苗接种所需的最短时间（至少一个月）和疫情的零星发生都强化了开发针对丝状病毒感染的有效小分子抑制剂的迫切需要。到识别并开发针对丝状病毒感染的有效抑制剂。对于丝状病毒爆发或生物恐怖袭击期间的使用至关重要，该申请定义了开发有效小分子抑制剂的计划，该抑制剂可阻止 EBOV 和 MARV 进入宿主细胞，这是由单一病毒糖蛋白介导的。 GP），被认为是主要的治疗靶点之一，GP由两个亚基组成，GP1和GP2负责受体结合和宿主向性，而GP2介导病毒/细胞。我们使用针对 GP 介导的病毒进入的 HTS 方案来筛选小分子库，并鉴定出抑制感染性 EBOV/MARV 进入的化合物（IC50 值 = 25 µM）。化合物对 EBOV/MARV 进入具有选择性。该 I 期申请的总体目标是开发这些抑制剂作为潜在的抗丝状病毒疗法。该申请将重点关注以下三个具体目标：（1）合成。 (2) 验证感染性疾病中的先导抑制剂并研究 EBOV/MARV 抑制剂的作用机制 (MOA)。 (3) 选择具有适合静脉注射和口服给药的体外 ADME 特性的 EBOV/MARV 抑制剂。