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

登革热病毒感染造成的沉重负担，加上缺乏有效的 疫苗或药物使新疗法的开发成为一个高度优先的问题。我们研究的目标是 识别和优化针对基本宿主因子的化合物，以加深我们对宿主病毒的理解 相互作用，并验证宿主目标和先导化合物作为潜在的新的进一步发展 抗病毒药物的类别。我们的战略是通过开发选择性的、共价的 半胱氨酸导向的抑制剂。共价抑制剂的成功已被三十九充分证明。 FDA批准的对人类高度有效的药物。 我们最近发现了一种替代的喹诺酮类药物QL-XII-47，它对四种登革热病毒有很强的抑制作用 血清型(EC90 400 Nm)在非细胞毒性浓度下。初步数据显示，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 获得抗病毒活性和获得具有合适药理特性的类似物所需的特征 使体内实验成为可能；(2)检查负责的靶点和作用机制 QL-XII-47及其相关化合物的体外抗病毒活性；(3)QL-XII-47和S的光谱检测 针对其他生物防御病毒的抗病毒活性。这项提议的目标是确定共价 主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，并在 登革热病毒感染的小鼠模型。该制剂的进一步发展及其分子的阐明 TARGET(S)可能为治疗登革热病毒感染提供首个宿主导向的药理学方法。 开发半胱氨酸导向的寄主因子共价抑制剂的策略可能提供一种新的和 开发宿主定向代理的通用范例，具有广泛防御多个 感染剂。

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.