Novel small molecule inhibitors of dengue replication

登革热复制的新型小分子抑制剂

• 批准号: 7676164
• 负责人: DENNIS E. HRUBY
• 金额: $ 55.93万
• 依托单位: SIGA TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-18 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7676164
• 关键词: Animals; Antibody-Dependent Enhancement; Antiviral Agents; Back; Biological; Biological Assay; Budgets; Cell physiology; Chemicals; Chemistry; Clinic; Contract Services; Control Groups; Critiques; Data; Dengue; Dengue Hemorrhagic Fever; Dengue Virus; Disease; Disease Outbreaks; Dose; Drug Kinetics; Ensure; Equilibrium; Evaluation; Excretory function; Face; Generations; Goals; Government; Infection; Lead; Letters; Libraries; Metabolism; Methods; Modeling; Modification; Mus; Outcome; Outsourcing; Pharmaceutical Chemistry; Public Health; Published Comment; Publishing; Readiness; Reporting; Research Personnel; Resources; Ribavirin; Risk; Scientist; Series; Serotyping; Structure-Activity Relationship; Suggestion; Therapeutic; Time; Vaccines; Vendor; Vertebrates; Viral; Viral Physiology; Virus; Virus Replication; absorption; analog; base; biodefense; cell type; cheminformatics; cost; design; disorder prevention; drug resistant virus; experience; high throughput screening; inhibitor/antagonist; interest; lead series; mouse model; novel; pre-clinical; programs; public health relevance; 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 both 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. Lead series will be defined by spectrum of activity, mechanism of action, preliminary absorption, distribution, metabolism, and excretion (ADME) profiles, and pharmacokinetic (PK) evaluations. Based upon the outcome of the biological characterizations, chemical tractability of related analogs, cheminformatic analyses, and nascent structure activity relationships, one or two lead compound series will be selected for chemical optimization to generate a preclinical candidate. PUBLIC HEALTH RELEVANCE: 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. .

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。一种能够在不增加 ADE 风险的情况下抑制病毒复制的抗病毒药物，通过提供控制疫情的手段，对公众健康以及用于生物防御准备的政府储备都极其有价值。 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。先导系列将通过活性谱、作用机制、初步吸收、分布、代谢和排泄 (ADME) 概况以及药代动力学 (PK) 评估来定义。根据生物学表征、相关类似物的化学易处理性、化学信息学分析和新生结构活性关系的结果，将选择一两个先导化合物系列进行化学优化，以产生临床前候选药物。公众健康相关性：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。 。