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Novel Therapeutic Strategies Targeting Re-emerging Alphaviruses

针对重新出现的甲病毒的新治疗策略

基本信息

批准号：
8650369
负责人：
DANIEL N STREBLOW
金额：
$ 110.61万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8650369
关键词：
Acute Affect Alphavirus Alphavirus Infections Antiviral Agents Area Arthralgia Arthropods Biological Assay Biological Availability Categories Cells Chemicals Complex Coronavirus Culicidae Development Disease Diversity Library Dose Drug Kinetics Encephalitis Enzymes Evaluation Event Exhibits FDA approved Family Flavivirus Generations Genome Goals Human Immune system Immunity In Vitro Indian Ocean Infection Inflammatory Influenza Interferons Lead Libraries Light Modeling Mus Mutate North America Nucleosides Nucleotides Pathology Pharmaceutical Chemistry Pharmaceutical Preparations Phenotype Population Property RNA Viruses RNA-Directed RNA Polymerase Research Resistance development Ribavirin Rivers Specificity Staging Syndrome Testing Therapeutic Therapeutic Agents Toxic effect Triage Vaccines Validation Viral Virulence Virus Virus Replication Western Equine Encephalomyelitis Work aged base biodefense cell type chikungunya clinically relevant cytotoxicity drug candidate drug development drug discovery efficacy testing forest high throughput screening in vivo indexing inhibitor/antagonist member mortality mutant nervous system disorder nonhuman primate novel novel therapeutics nucleoside analog nucleotide analog pathogen prevent programs research study response scaffold screening small molecule small molecule libraries therapy development transmission process vector

项目摘要

The main goal of our Project (3) is to develop novel nucleoside and nucleotide inhibitors directed against Alphaviruses. There is a very important need for the development of treatments against these important human pathogens. We propose to identify potent inhibitors of CHIKV and VEEV replication by performing a high-throughput screen with chemical libraries from Gilead (50,000 heterocycles and nucleoside analogs), HitCreate library from Tranzyme (50,000 macrocycles) and the Diversity Library (27,000 heterocycles). Compounds displaying activity against the two viruses will be further validated and then characterized for specificity within the Alphavirus genus, efficacy and toxicity in multiple relevant cell-types, mode of action, and generation of viral mutants. Compounds that pass this second set of filters will undergo Hit to lead optimization and SAR with subsequent retesting in secondary screens. Last of all, we will perform in vivo efficacy testing in relevant mouse and non-human primate models of alphavirus infection and disease for compounds with good bioavailability and activity. Through these studies we will develop robust antiviral agents against multiple members of the Alphavirus genus.

我们项目（3）的主要目标是开发针对甲病毒的新型核苷和核苷酸抑制剂。非常需要开发针对这些重要的人类病原体的治疗方法。我们提出通过用来自吉利德的化学文库（50，000个杂环和核苷类似物）、来自Tranzyme的HitCreate文库（50，000个大环）和多样性文库（27，000个杂环）进行高通量筛选来鉴定CHIKV和VEEV复制的有效抑制剂。将进一步验证对两种病毒显示活性的化合物，然后表征甲病毒属内的特异性、多种相关细胞类型中的功效和毒性、作用模式和病毒突变体的产生。通过第二组过滤器的化合物将进行Hit以引导优化和SAR，随后在二级筛选中重新测试。最后，我们将在甲病毒感染和疾病的相关小鼠和非人灵长类动物模型中对具有良好生物利用度和活性的化合物进行体内功效测试。通过这些研究，我们将开发针对甲病毒属多个成员的强大抗病毒剂。