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: 8366564
• 负责人: VISHWANATH R LINGAPPA
• 金额: $ 33.07万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8366564
• 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; Screening procedure; 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; 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. PUBLIC HEALTH RELEVANCE: Rabies is a disease that, once contracted, is almost universally fatal. Over 30,000 people die yearly worldwide and many more are at risk. There are significant limitations of the available vaccines that a small molecule, effective against the viru even after onset of clinical symptoms, would ameliorate. We have identified a small molecule with good activity against rabies virus in cell culture that we propose to advance to protect animals, a key step before taking the advanced drug to the FDA.

描述（由申请人提供）：我们采用了一种新的抗病毒药物发现方法，利用无细胞蛋白质合成为导致人类疾病的 23 个病毒家族中的 20 个病毒重建宿主催化的衣壳组装途径。其中十种已适应中等通量的全途径筛选，通过这些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。大量使用这种方法 对于所研究的每个病毒家族，已鉴定出在细胞培养物中具有针对感染性病毒的有效活性的不同药效团。先进的类似物显示出效力的显着提高，同时毒性的降低，表明功效和毒性之间存在明显的构效关系（SAR）。先进的类似物还被用作亲和层析的配体来识别宿主靶标。这些宿主靶标已被证明包含显示出显着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所修饰，因此解释了我们有能力通过病毒靶向使用它们，而不会对宿主产生显着的毒性。这导致了许多先导系列的鉴定，其选择性指数（CC50/EC50，SI）> 100。这些先进化合物显示出一些与其针对宿主靶标的活性一致的不寻常特性：一般来说，它们对病毒家族的所有成员都有效，没有证据表明病毒产生耐药性。在这里，我们建议推进在狂犬病病毒 (RABV) 衣壳组装的无细胞全途径筛选中鉴定的小分子先导系列，该小分子先导系列对细胞培养中的感染性 RABV 具有有效的活性。 SAR 将用于该项目的 R21 阶段，以实现效力的适度进步和毒性的降低，从而将 SI 从 50-100 提高到 >100。我们还将优化药代动力学和药效 (PK/PD) 特性，足以证明 R33 成分下的进展是合理的，以使用小鼠在暴露前模型中进行概念动物功效测试。一旦成功，进一步的 R33 研究将推动最有效的化合物用于 RABV 感染仓鼠模型的暴露后预防，并根据需要进行额外的先导优化。拟议的工作将通过在两种脊椎动物中实现动物疗效来推进 RABV 小分子疗法，并通过足够的暴露来支持每日一次或两次给药，从而为未来的 IND 支持研究奠定基础。 公众健康相关性：狂犬病是一种一旦感染几乎会致命的疾病。全球每年有超过 30,000 人死亡，还有更多人面临危险。现有疫苗存在显着的局限性，即使在临床症状出现后，小分子也能有效对抗病毒，从而改善这种局限性。我们在细胞培养物中发现了一种对狂犬病病毒具有良好活性的小分子，我们建议将其用于保护动物，这是将该先进药物提交 FDA 之前的关键一步。