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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要由蚊子α/west-引起的新兴病毒感染，例如委内瑞拉/西部 - ERN/东马脑炎病毒（VEEV，EEEV或WEEV）和Chikungunya病毒是织机威胁世界各地的公共卫生系统。没有疫苗或治疗药物被证明是针对α病毒的人类使用的，我们对分子的了解有限大多数α病毒的致病性。如果区域性或跨国爆发α病毒感染在将来发生，可以最大程度地减少或阻止生命损失和经济生产力的损失如果有治疗或预防剂。在此应用中，我们提出了一个研究进入一系列新的分子，该分子抑制非结构蛋白的蛋白酶结构域 VEEV的2（NSP2）阻止了人类细胞中VEEV的复制，并且适合系统对于药物开发很重要的结构变化。该项目的主要目标是：（a）。使用多参数研究NSP2的基于共价和机制的可逆抑制剂结构活性研究关系（SAR）研究以及互补代谢和生物利用度研究；（b）。研究分子之间的分子相互作用和NSP2使用晶体学和分子建模，这将促进目标特异性操作毒品候选者的围攻。项目目标将促进com的进步对临床前研究的磅序列，作为具有抗al-的第一类NSP2抑制剂与生理相关浓度的假病毒活性。另外，分子将还可以作为有价值的分子工具来促进我们对NSP2的作用的理解 α病毒的致病性。