Antiviral therapeutics for flavivirus infections

黄病毒感染的抗病毒治疗

• 批准号: 8461110
• 负责人: DENNIS E. HRUBY
• 金额: $ 115.21万
• 依托单位: SIGA TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-03 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461110
• 关键词: Animal Model; Animals; Antibody-Dependent Enhancement; Antiviral Agents; Applications Grants; Biochemical; Biological; Biological Assay; Biological Availability; Biological Products; Categories; Cell Culture Techniques; Characteristics; Chemicals; Chemistry; Controlled Study; Data; Dengue; Dengue Hemorrhagic Fever; Dengue Virus; Development; Disease; Disease Outbreaks; Drug Exposure; Drug Formulations; Drug Kinetics; Drug Stability; Drug or chemical Tissue Distribution; Drug resistance; Equilibrium; Evaluation; Excretory function; Face; Flavivirus; Flavivirus Infections; Funding; Genetic; Goals; Government; Human; In Vitro; Infection; Investigational Drugs; Investigational New Drug Application; Lead; Libraries; Metabolic; Metabolism; Molecular; Monitor; Oral; Oral Administration; Pharmaceutical Preparations; Pharmacology; Physiology; Population; Predisposition; Process; Property; Public Health; Readiness; Risk; Safety; Series; Serotyping; Structure-Activity Relationship; Therapeutic; Toxic effect; Toxicology; Vaccines; Variant; Viral; Virulence; Virus; Virus Diseases; Virus Replication; Work; absorption; analog; analytical method; animal efficacy; base; biodefense; disorder prevention; drug candidate; drug metabolism; drug resistant virus; drug synthesis; fitness; high throughput screening; improved; inhibitor/antagonist; lead series; pathogen; pre-clinical; programs; protective efficacy; scale up; small molecule; vaccine development

DESCRIPTION (provided by applicant): There is an urgent need for new antivirals for both treatment and control of dengue virus, given that over 50 million people are infected worldwide with dengue every year, including 500,000 cases of the more severe form of the disease, dengue hemorrhagic fever (DHF) and there are no approved vaccines or antiviral drugs available. Vaccine development is promising but faces several significant challenges including the need to balance protection against all four serotypes of the virus equally in order to avoid antibody-dependent enhancement of infection and risk of DHF. An antiviral drug that inhibits viral replication without increasing the risk for ADE would be extremely valuable for public health by providing a means to control outbreaks, as well as to government stockpiles for biodefense preparedness. The overall goal of the SIGA dengue program is to develop a small molecule therapeutic for the treatment and/or prevention of disease caused by dengue virus. A sensitive and specific high throughput screening (HTS) assay has been developed to evaluate compounds from the SIGA chemical compound library for inhibitory activity against dengue-2 (DEN-2) virus replication. Hits have been identified that are potent (EC50<5uM) and selective (CC50>25uM), with initial structure activity relationship in several series of related compounds. Quality hits were characterized for spectrum of activity, mechanism of action (MOA), preliminary absorption, distribution, metabolism and excretion (ADME) properties, preliminary biopharmaceutical properties, and tolerability. Based on this characterization two lead series were identified that have an optimal biological profile consistent with development of an anti-dengue drug. In this application chemical analogs of selected quality hits will be synthesized to improve the properties of the compounds leading to the nomination of a preclinical candidate which will enter into IND-enabling toxicology.

描述（由申请人提供）：鉴于全球每年有超过 5000 万人感染登革热，其中包括 50 万例更严重的登革热病例，因此迫切需要新的抗病毒药物来治疗和控制登革热病毒。登革出血热 (DHF)，目前尚无批准的疫苗或抗病毒药物。疫苗开发前景广阔，但面临一些重大挑战，包括需要平衡对所有四种病毒血清型的保护，以避免抗体依赖性感染增强和 DHF 风险。一种抑制病毒复制而不增加 ADE 风险的抗病毒药物将提供一种控制疫情的手段，对公众健康极其有价值，并为政府储备生物防御准备。 SIGA 登革热计划的总体目标是开发一种小分子疗法，用于治疗和/或预防由登革热病毒引起的疾病。 我们开发了一种灵敏且特异的高通量筛选 (HTS) 测定法，用于评估 SIGA 化合物库中的化合物对登革热 2 (DEN-2) 病毒复制的抑制活性。已确定有效 (EC50<5uM) 和选择性 (CC50>25uM) 的命中，并在几个相关化合物系列中具有初始结构活性关系。质量命中的特征包括活性谱、作用机制 (MOA)、初步吸收、分布、代谢和排泄 (ADME) 特性、初步生物制药特性和耐受性。基于这一特征，确定了两个先导系列，它们具有与抗登革热药物开发一致的最佳生物学特征。在此应用中，将合成选定优质命中的化学类似物，以改善化合物的特性，从而提名临床前候选药物，该候选药物将进入支持 IND 的毒理学研究。