Advancement of Novel Small Molecules for Treatment of Rabies

新型小分子治疗狂犬病的进展

• 批准号: 8484791
• 负责人: VISHWANATH R LINGAPPA
• 金额: $ 11.1万
• 依托单位: PROSETTA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-08 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8484791
• 关键词: Accounting; Affinity Chromatography; Animals; Antiviral Agents; Biological Availability; Blood - brain barrier anatomy; Capsid; Cell Culture Techniques; Cells; Clinical; Clinical Trials; Contracts; Cytochrome P450; Data; Disease; Dose; Drug Interactions; Drug Kinetics; Exposure to; Family; Family Study; Future; Goals; Hamsters; Human; Integration Host Factors; Investigational Drugs; Lead; Libraries; Ligands; Liver Microsomes; Mammalian Cell; Measures; Modeling; Mus; Nature; Neuraxis; Oral; Pathway interactions; Penetration; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Phase; Property; Prophylactic treatment; Protein Binding; Protein Biosynthesis; Protocols documentation; Rabies; Rabies virus; Resistance development; Risk; Route; Specificity; Staging; Structure-Activity Relationship; Symptoms; Testing; Therapeutic; Toxic effect; Vaccines; Validation; Viral; Virus; Virus Diseases; Work; analog; animal efficacy; drug development; drug discovery; efficacy testing; human disease; improved; indexing; lead series; member; novel; novel strategies; pharmacophore; pre-clinical; prophylactic; protein protein interaction; screening; small molecule; success; viral resistance

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.

描述（由申请人提供）：我们已经采取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重建引起人类疾病的23个病毒家族中的20个的宿主催化衣壳组装途径。其中10个已经适应于中等通量全途径筛选，通过该筛选可以鉴定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， 对于所研究的每个病毒家族，已经在细胞培养物中鉴定出了对感染性病毒具有强效活性的不同药效团。高级类似物显示效力的实质性改善，伴随着毒性的降低，表明功效和毒性的不同结构-活性关系（SAR）。先进的类似物也已被用作亲和层析的配体，以识别宿主靶标。这些宿主靶标已被证明包含显示出显著程度的病毒特异性的组装机器：它们似乎被组装的底物的性质修饰，因此解释了我们靶向病毒使用它们的能力，而对宿主没有显著毒性。这导致了许多铅系列的鉴定，选择性指数（CC 50/EC 50，SI）> 100。先进的化合物显示出一些不寻常的特性，与它们对宿主靶点的活性一致：一般来说，它们对病毒家族的所有成员都有效，没有病毒耐药性发展的证据。在这里，我们提出了一个小分子的铅系列确定在无细胞的全途径筛选狂犬病病毒（RABV）衣壳组装，具有有效的活性，对感染性RABV在细胞培养。SAR将用于该项目的R21阶段，以实现将SI从50-100提高到>100所需的效价和毒性降低的适度进展。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组分下的进展，以证明在使用小鼠的预暴露模型中进行动物疗效试验的概念。一旦成功，进一步的R33研究将推进最有效的化合物在RABV感染的仓鼠模型中进行暴露后预防，并根据需要进行额外的先导化合物优化。拟议的工作将通过在两种脊椎动物物种中实现动物疗效来推进RABV小分子治疗，并有足够的暴露量来支持每日一次或两次给药，从而为未来的IND研究奠定基础。