Antiviral therapeutics for flavivirus infections

黄病毒感染的抗病毒治疗

• 批准号: 8076148
• 负责人: DENNIS E. HRUBY
• 金额: $ 144.28万
• 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/8076148
• 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）：迫切需要新的抗病毒药对登革热病毒的治疗和控制，鉴于每年有超过5000万人在全球范围内被登革热感染，其中包括500,000例疾病更严重的疾病形式，登革热大量造成的登革热疫苗（DHF），并且没有批准的疫苗或抗病毒药物。疫苗开发是有希望的，但面临着一些重大挑战，包括需要平衡对病毒的所有四种血清型平衡，以避免抗体依赖性感染的增强和DHF风险。一种抑制病毒复制的抗病毒药物而不会增加ADE风险，这对于公共卫生而言非常有价值，可以通过控制暴发的手段，以及为Biodefense准备的政府库存准备。 SIGA登革热计划的总体目标是开发一种用于治疗和/或预防登革热病毒疾病的小分子治疗。 已经开发了一种敏感且特异性的高吞吐量筛选（HTS）测定法，以评估SIGA化学复合文库中的化合物，以抑制对登革热-2（DEN-2）病毒复制的抑制活性。已经确定了有效的（EC50 <5UM）和选择性（CC50> 25UM）的命中，并在几个系列相关化合物中具有初始结构活动关系。质量命中的特征是活性，作用机理（MOA），初步吸收，分布，代谢和排泄（ADME）特性，初步的生物制药特性和耐受性。基于此特征，鉴定了两个铅系列，具有与抗登记药物的开发一致的最佳生物学特征。在这种应用中，将合成选定质量命中的化学类似物，以提高化合物的性能，从而提名临床前候选者，该临床前候选者将进入辅助毒理学。