Host-Targeted, Irreversible Inhibitors of Dengue Virus and Biodefense Viruses

登革热病毒和生物防御病毒的针对宿主的不可逆抑制剂

• 批准号: 8566287
• 负责人: NATHANAEL Schiander GRAY
• 金额: $ 15.3万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8566287
• 关键词: Acrylamides; Affect; Affinity; Affinity Chromatography; Alkynes; Animal Model; Antibiotics; Antiviral Agents; Antiviral Therapy; Area; Binding; Biological; Biological Assay; Biology; Categories; Chemicals; Chemistry; Culicidae; Cysteine; Data; Dengue; Dengue Hemorrhagic Fever; Dengue Virus; Development; Dose; Drug Exposure; Drug Kinetics; Epidemic; Evaluation Studies; Exhibits; FDA approved; Family; Flavivirus; Future; Gene Expression; Goals; Heterocyclic Compounds; Human; In Vitro; Infection; Infectious Agent; Integration Host Factors; Lead; Libraries; Life; Measures; Mediating; Modeling; Molecular Target; Monitor; Mus; National Institute of Allergy and Infectious Disease; New England; Pathway interactions; Penicillins; Peptidyltransferase; Pharmaceutical Chemistry; Pharmaceutical Preparations; Post-Translational Modification Site; Property; Proteins; Proteomics; Public Health; Quinolones; RNA replication; Research; Resistance; Risk; Screening procedure; Serotyping; Site-Directed Mutagenesis; Streptavidin; Structure-Activity Relationship; Therapeutic; Toxicology; Vaccines; Viral; Virus; Virus Diseases; Work; analog; biodefense; cytotoxicity; design; efficacy evaluation; human disease; in vitro activity; in vivo; inhibitor/antagonist; novel therapeutics; particle; pathogen; prevent; research study; response; small molecule; success; transmission process; virology; virus host interaction

The significant burden that results from dengue virus infection combined with the absence of effective vaccines or drugs makes the development of novel therapeutics a high priority. The goal of our research is to identify and optimize compounds that target essential host factors to further our understanding of host-virus interactions and to validate host targets and ¿lead¿ compounds for further development as potential new classes of anti-viral agents. Our strategy is to target essential host factors by developing selective, covalent cysteine-directed inhibitors. The success of covalent inhibitors has been amply demonstrated by the thirtynine FDA-approved drugs that are highly effective in humans. We recently discovered a substituted quinolone, QL-XII-47, that is a potent inhibitor of the four dengue serotypes (EC90 400nM) at concentrations that are non-cytotoxic. Preliminary data indicate that QL-XII-47 acts via a host factor to inhibit DENV at a point late in viral entry. QL-XII- 47 has exhibited inhibitory activity against a number of other viruses within and beyond the Flavivirus family. We will utilize a combination of medicinal chemistry, chemical biology, chemical proteomics, and virology (1) to understand the structural features required to achieve antiviral activity and to obtain analogs with suitable pharmacological properties to enable in vivo experiments; (2) to examine the target and mechanism of action responsible for the potent antiviral activity of QL-XII-47 and related compounds in vitro; and (3) to examine the spectrum of QL-XII-47¿s antiviral activities against additional Biodefense Viruses. The goal of this proposal is to identify covalent inhibitors of essential host-factor targets that exhibit broad antiviral activity in vitro and that are efficacious in a murine model of dengue virus infection. Further development of this agent and elucidation of its molecular target(s) may provide the first host-directed pharmacological approach for treating dengue virus infection. The strategy of developing cysteine-directed covalent inhibitors of host factors may provide a new and general paradigm for developing host-directed agents with the potential to broadly protect against many infectious agents.

登革热病毒感染加上缺乏有效的治疗措施造成的巨大负担 疫苗或药物使新型疗法的开发成为当务之急。我们研究的目标是 识别和优化针对重要宿主因素的化合物，以进一步了解宿主病毒 相互作用并验证宿主靶点和“先导”化合物，以进一步开发为潜在的新化合物 抗病毒药物的类别。我们的策略是通过开发选择性、共价键来针对重要的宿主因子 半胱氨酸定向抑制剂。三十九项研究充分证明了共价抑制剂的成功 FDA 批准的药物对人类非常有效。 我们最近发现了一种取代喹诺酮 QL-XII-47，它是四种登革热的有效抑制剂 血清型 (EC90 400nM) 在非细胞毒性浓度下。初步数据表明，QL-XII-47 通过宿主因子发挥作用，在病毒进入后期抑制 DENV。 QL-XII-47 表现出抑制活性 对抗黄病毒家族内外的许多其他病毒。我们将结合使用 药物化学、化学生物学、化学蛋白质组学和病毒学 (1) 了解结构 实现抗病毒活性和获得具有合适药理学特性的类似物所需的特征 进行体内实验； (2) 考察有效作用的靶点和作用机制 QL-XII-47和相关化合物的体外抗病毒活性； (3) 检查 QL-XII-47 的光谱 针对其他生物防御病毒的抗病毒活性。该提案的目标是识别共价键 重要宿主因子靶标的抑制剂，在体外表现出广泛的抗病毒活性，并且在以下方面有效： 登革热病毒感染的小鼠模型。该药物的进一步开发及其分子的阐明 靶点可能为治疗登革热病毒感染提供第一个针对宿主的药理学方法。 开发针对宿主因子的半胱氨酸共价抑制剂的策略可能提供新的和 开发具有广泛保护免受许多侵害的潜力的宿主导向代理的一般范例 传染源。