Advancement of Novel Small Molecules for Treatment of Rabies

描述(申请人提供)：我们采用了一种新的方法来发现抗病毒药物，使用无细胞蛋白质合成来为导致人类疾病的23个病毒家族中的20个重建宿主催化的衣壳组装途径。其中10个已经适应于中等吞吐量的全途径筛选，通过这些筛选可以识别干扰该途径中蛋白质-蛋白质相互作用的小分子。使用这种方法是多余的 对于每个被研究的病毒家族，已经在细胞培养中确定了具有强大抗传染性病毒活性的不同的药效团。先进的类似物显示，效力的大幅提高伴随着毒性的降低，这表明疗效和毒性具有明显的结构-活性关系(SAR)。先进的类似物也被用作亲和层析的配基，以识别宿主目标。这些宿主靶标已被证明包括表现出显著程度的病毒特异性的组装机：它们似乎被组装的底物的性质所修饰，从而解释了我们有能力靶向病毒对它们的使用，而对宿主没有显著的毒性。这导致了许多具有选择性指数(CC50/EC50，SI)和GT；100的铅系列的鉴定。这些先进的化合物表现出一些与它们对宿主靶标的活性一致的不同寻常的性质：通常，它们对病毒家族的所有成员都有效，没有证据表明病毒抗药性的发展。在这里，我们建议推进在狂犬病病毒(RABV)衣壳组件的无细胞全程筛选中鉴定的小分子先导系列，该组件在细胞培养中具有强大的抗传染性RABV活性。合成孔径雷达将用于该项目的R21阶段，以在效力和降低毒性方面取得适度进展，这是将SI从50-100提高到&gt；100所必需的。我们还将优化药代动力学和药效学(PK/PD)特性，足以证明在R33成分下的进步是合理的，以证明在使用小鼠的暴露前模型中进行动物功效测试的概念。一旦成功，进一步的R33研究将推进最有效的化合物在暴露后预防RABV感染的仓鼠模型中，并根据需要进行额外的先导优化。拟议的工作将推进RABV小分子疗法，在两个脊椎动物物种上实现动物疗效，并充分暴露于支持每天一到两次剂量，从而为未来的IND研究奠定基础。

DESCRIPTION (provided by applicant): We have taken a novel approach to antiviral drug discovery, using cell-free protein synthesis to recreate the host-catalyzed capsid assembly pathways for 20 of the 23 families of viruses causing human disease. Ten of these have been adapted to moderate throughput whole pathway screens by which small molecules that interfere with protein-protein interactions in this pathway can be identified. Using this approach a plethora of distinct pharmacophores with potent activity against infectious virus in cell culture has been identified, for every viral family studied. Advanced analogs reveal substantial improvement in potency with concomitant diminution in toxicity, suggesting distinct structure-activity relationships (SAR) for efficacy and toxicity. The advanced analogs have also been used as ligands for affinity chromatography to identify the host targets. These host targets have been shown to comprise assembly machines that show a remarkable degree of viral specificity: they appear to be modified by the nature of the substrate being assembled, hence accounting for our ability to target their use by the virus, without significant toxicity to the host. This has resultd in identification of numerous lead series' with selectivity indices (CC50/EC50, SI) > 100. The advanced compounds display some unusual properties consistent with their activity against host targets: in general, they are effective against all members of a viral family, with no evidence of viral resistance development. Here we propose to advance a small molecule lead series identified in a cell-free whole pathway screen for rabies virus (RABV) capsid assembly that has potent activity against infectious RABV in cell culture. SAR will be used in the R21 phase of the project to achieve modest advances in potency and diminution of toxicity necessary to improve the SI from 50-100 to >100. We will also optimize pharmacokinetic and pharmacodynamic (PK/PD) properties sufficient to justify advancement under the R33 component to proof of concept animal efficacy testing in a pre-exposure model using mice. Upon success, further R33 studies will advance the most efficacious compounds to post-exposure prophylaxis in the hamster model of RABV infection, with additional lead optimization, as needed. The proposed work will advance RABV small molecule therapeutics by achieving animal efficacy in two vertebrate species, with adequate exposure to support once or twice daily dosing, thereby setting the stage for future IND-enabling studies.