Lead Optimization of ML336, a Potent VEEV Inhibitor

有效 VEEV 抑制剂 ML336 的先导化合物优化

• 批准号: 9460361
• 负责人: Donghoon Chung
• 金额: $ 65.55万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9460361
• 关键词: Address; Alphavirus; Americas; Amidines; Antiviral Agents; Asses; Biodistribution; Biotechnology; Chemicals; Chemistry; Consultations; Disease; Dose; Drug Kinetics; Encephalitis; Equus caballus; Future; Human; In Vitro; Knowledge; Lead; Metabolic; Molecular Bank; Mus; Nonstructural Protein; Outcome; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Preclinical Drug Development; Property; RNA Viruses; RNA chemical synthesis; Regimen; Replication-Associated Process; Research; Research Design; Research Methodology; Resistance; Series; Solubility; Structure; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Trinidad; United States National Institutes of Health; Vaccines; Venezuelan; Venezuelan Equine Encephalitis Virus; Virus Inhibitors; Western Equine Encephalitis Virus; analog; cytotoxicity; efficacy study; efficacy testing; health economics; high throughput screening; improved; in vitro Assay; in vitro activity; in vivo; insight; interest; lead candidate; lead optimization; mouse model; novel; pathogen; pre-clinical; preclinical study; public health relevance; replicase; research clinical testing; small molecule; small molecule therapeutics; therapeutic candidate; viral RNA; viral resistance

 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.

 描述（由申请方提供）：委内瑞拉新世界甲病毒（VEEV）、东部和西部马脑炎病毒是美洲流行的新兴病原体。它们在人类和马中引起脑炎，从而造成严重的健康和经济问题。尽管迫切需要，但目前还没有批准的药物或疫苗可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ML 336的类似物，这是一种有前途的先导化合物，作为未来针对VEEV和其他甲病毒引起的疾病的临床评价的小分子治疗候选物。具体目标/假设：具体目标涉及两个假设。在目标1和2中，我们假设ML 336的药物化学优化可以提供一种安全和特异性的临床前治疗候选药物来治疗新世界甲病毒疾病。在目标3中，我们检验了ML 336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：目的1通过构效关系和构效关系（SAR-SPR）研究，获得适合体内药效的稳健药理学特征。具体而言，Golden博士将努力生产具有改善的药理学特征的ML 336类似物，包括增加溶解度和BBB渗透性以及降低代谢倾向，以改善暴露和清除参数。在目标2中，郭博士将每年评估ML 336和2-3种先导化合物的生物分布和药代动力学/动力学，显示合适且稳健的药理学和抗病毒（体外和体内）特征。Jonsson博士将领导两项最有前途的 引导候选人使用VEEV Trinidad Donkey毒株确定最佳给药方案。最后，Dr. Chung将与Dr. Sawicki协商，使用以复制为重点的体外试验（目标3）剖析ML 336的作用机制。