Hit to Lead Optimization of Non-Peptidic Inhibitors of Alphaviral Cysteine Protease

甲病毒半胱氨酸蛋白酶非肽抑制剂的优化

• 批准号: 10682095
• 负责人: JOSEPH A WHITTAKER
• 金额: $ 25.91万
• 依托单位: JACKSON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10682095
• 关键词: Alphavirus; Alphavirus Infections; Binding; Biochemical; Biological Availability; Capsid Proteins; Caspase; Cell Membrane Permeability; Cells; Chemicals; Chikungunya virus; Communities; Complex; Country; Crystallization; Crystallography; Culicidae; Data Discovery; Disease; Disease Outbreaks; Eastern Equine Encephalitis Virus; Economics; FDA approved; Fever; Future; Genetic Transcription; Genome; Global Warming; Glycoproteins; Goals; Health system; Human; Hydrolysis; In Vitro; Infection; Investigation; Kinetics; Knowledge; Lead; Life; Life Expectancy; Metabolic; Methyltransferase; Molecular; Nonstructural Protein; Open Reading Frames; Pathogenicity; Peptides; Pharmaceutical Preparations; Phenotype; Physiological; Play; Polyproteins; Preclinical Drug Development; Productivity; Property; Protease Domain; Proteins; Public Health; RNA; RNA chemical synthesis; Research Personnel; Resolution; Risk; Role; Series; Solubility; Structure; Structure-Activity Relationship; Testing; Therapeutic; Therapeutic Intervention; Time; Translating; Vaccines; Venezuelan; Venezuelan Equine Encephalitis Virus; Viral; Viral Genome; Viral Structural Proteins; Virion; Virulent; Virus; Virus Diseases; Virus Replication; Western Equine Encephalitis Virus; Work; antipyretic; aqueous; base; clinical candidate; design; drug development; efficacy study; electrophilic substitution; genomic RNA; improved; in vitro activity; in vivo; in vivo evaluation; inhibitor; lead candidate; lead optimization; molecular modeling; mosquito-borne; pathogenic virus; pharmacophore; polypeptide; pre-clinical; preclinical study; prevent; prophylactic; quinoline; screening; small molecule; small molecule inhibitor; small molecule therapeutics; targeted agent; tool; transmission process; viral RNA

Project Summary Emerging viral infections caused by mosquito-borne alphaviruses such as Venezuelan/West- ern/Eastern equine encephalitis virus (VEEV, EEEV or WEEV) and Chikungunya virus are loom- ing threats to public health systems around the world. There are no vaccines or therapeutics ap- proved for human use against alphaviruses, and we have limited understanding of the molecular pathogenicity of most alphaviruses. If regional or transnational outbreak of alphavirus infections occur in the future, loss of life and loss of economic productivity can be minimized or prevented if therapeutic or prophylactic agents are available. In this application, we propose an investiga- tion into a new series of molecules that inhibit the protease domain of the non-structural protein 2 (nsP2) of VEEV, blocks the replication of VEEV in human cells, and are amenable to systematic structural changes that is important for drug development. The main goals of this project are: (a). To investigate covalent and mechanism-based reversible inhibitors of nsP2 using multiparameter structure-activity studies relationships (SAR) studies along with complementary metabolic and bioavailability studies; and (b). To investigate the molecular interactions between the molecules and nsP2 using crystallography and molecular modelling, which will facilitate target-specific op- timization of drug lead candidates. The project goals will facilitate the advancement of the com- pound series towards preclinical investigation as first-in-class nsP2 inhibitors that have anti-al- phaviral activities at physiologically relevant concentrations. Additionally, the molecules will also serve as valuable molecular tools to advance our understanding of the role of nsP2 in the pathogenicity of alphaviruses.

项目摘要 由蚊媒甲病毒引起的新出现的病毒感染，如委内瑞拉/西- 欧洲/东部马脑炎病毒（VEEV，EEEV或WEEV）和基孔肯雅病毒是迫在眉睫的。 威胁到世界各地的公共卫生系统。目前还没有疫苗或治疗方法- 已经被证明可以用于人类对抗甲病毒，我们对这种病毒的分子机制的了解有限。 大多数甲病毒的致病性。如果甲病毒感染的区域或跨国爆发 如果将来发生这种情况，生命损失和经济生产力损失可以最大限度地减少或避免 如果治疗或预防剂是可用的。在本申请中，我们提出了一种新的方法- 转化为一系列新的分子，抑制非结构蛋白的蛋白酶结构域 2（nsP 2），阻断VEEV在人细胞中的复制，并且适于系统性地 结构变化对药物开发很重要。该项目的主要目标是：（a）。 使用多参数研究nsP 2的共价和基于机理的可逆抑制剂 构效关系（SAR）研究沿着补充代谢和 生物利用度研究;和（B）.研究分子间的分子相互作用 和nsP 2使用晶体学和分子建模，这将有助于目标特异性操作， 药物主要候选人的最佳化。该项目的目标将促进该com- 磅系列作为一类具有抗α 1 β 2抑制剂的nsP 2抑制剂进行临床前研究， 在生理相关浓度下的甲病毒活性。此外，分子将 也作为有价值的分子工具，以促进我们对nsP 2在肿瘤中作用的理解。 甲病毒的致病性。