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

登革病毒感染加上缺乏有效的预防措施， 疫苗或药物的开发使得新疗法的开发成为高度优先事项。我们研究的目的是 鉴定和优化靶向必需宿主因子的化合物，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 抗病毒药物的种类。我们的策略是通过开发选择性的，共价的， 半胱氨酸定向抑制剂。共价抑制剂的成功已经被39个 FDA批准的对人类非常有效的药物。 我们最近发现了一种取代的喹诺酮，QL-XII-47，它是四种登革热病毒的有效抑制剂， 血清型（EC 90 400 nM），浓度为非细胞毒性。初步数据表明，QL-XII-47 通过宿主因子在病毒进入后期抑制DENV。QL-XII- 47具有抑制活性， 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性质的类似物所需的特征 使体内实验;（2）检查靶点和作用机制，负责有效的 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 对其他生物防御病毒的抗病毒活性。该提案的目标是确定共价键 在体外表现出广泛的抗病毒活性并有效地 登革病毒感染的鼠模型。该制剂的进一步开发及其分子结构的阐明 靶点可以提供用于治疗登革病毒感染的第一种针对宿主的药理学方法。 开发半胱氨酸靶向的宿主因子共价抑制剂的策略可能提供一种新的， 开发具有广泛防御多种病毒的潜力的宿主导向剂的一般范例 传染源

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.