Lead Optimization of ML336, a Potent VEEV Inhibitor

 描述(申请人提供)：新世界甲型病毒，委内瑞拉(VEEV)，东部和西部马脑炎病毒，是在整个美洲流行的新出现的病原体。它们会引起人和马的脑炎，从而带来严重的健康和经济问题。尽管迫切需要，但无论是批准的药物还是疫苗都不能用于治疗人类的这些疾病。广泛的长期目标：本文所述的研究目标以及基于这些发现的未来研究将提供ML336的类似物，ML336是一种有前途的先导化合物，作为未来针对VEEV和其他甲型病毒引起的疾病的临床评估的小分子候选药物。具体目标/假设：具体目标涉及两个假设。在目标1和目标2中，我们假设ML336的药物化学优化可以为治疗新世界甲型病毒病提供安全和特异的临床前候选药物。在目标3中，我们测试了ML336通过破坏复制酶组装所需的相互作用和/或直接抑制病毒RNA合成所需的酶活性来阻断VEEV RNA合成的假设。研究设计和方法：目标1将通过结构-活性和结构-性质关系(SAR-SPR)研究得出适合体内疗效的强大药理特性。具体地说，戈登博士将领导努力开发具有改进的药理特性的ML336类似物，包括增加溶解度和血脑屏障通透性，降低代谢倾向，以改善暴露和清除参数。在目标2中，郭博士将每年评估ML336和2-3先导化合物的生物分布和药代动力学/动力学，显示出合适和强大的药理和抗病毒(体外和体内)概况。琼森博士将领导两项最有希望的体内疗效测试研究 引导候选人使用VEEV特立尼达驴株确定最佳给药方案。最后，钟博士将与Sawicki博士协商，使用专注于复制的体外试验(Aim 3)剖析ML336的作用机制。

 DESCRIPTION (provided by applicant): The New World alphaviruses, Venezuelan (VEEV), Eastern and Western Equine Encephalitis viruses, are emerging pathogens that are endemic throughout the Americas. They cause encephalitis in humans and equines, thus presenting serious health and economic problems. Despite the urgent need, neither approved drugs nor vaccines are available for treatment of these diseases in humans. Broad, long-term objectives: The research objectives stated herein, and in future studies that build upon these findings, will deliver analogs of ML336, a promising lead compound, as small molecule therapeutic candidates for future clinical evaluation targeting diseases caused by VEEV and other alphaviruses. Specific aims/hypothesis: The specific aims address two hypotheses. In aims 1 and 2, we hypothesize that medicinal chemical optimization of ML336 can afford a safe and specific therapeutic preclinical candidate to treat New World alphaviral diseases. In aim 3, we test the hypothesis that ML336 blocks VEEV RNA synthesis through disruption of interactions required for replicase assembly and/or directly inhibits an enzymatic activity required for viral RNA synthesis. Research design and methods: Aim 1 will derive a robust pharmacological profile suitable for in vivo efficacy through structure-activity and structure-property relationshi (SAR-SPR) studies. Specifically, Dr. Golden will lead efforts to generate analogs of ML336 with an improved pharmacological profile that includes increased solubility and BBB permeability and reduced metabolic liability to improve exposure and clearance parameters. In Aim 2, Dr. Guo will assess the biodistribution and pharmacokinetics/dynamics of ML336 and 2-3 lead compounds each year showing suitable and robust pharmacological and antiviral (in vitro and in vivo) profiles. Dr. Jonsson will lead in vivo efficacy testing studies of two of the most promising lead candidates to define the optimal dosing regimen using the VEEV Trinidad Donkey strain. Finally, Dr. Chung will dissect the mechanism of action of ML336 using in vitro assays focused on replication (Aim 3) in consultation with Dr. Sawicki.