Discovery and development of novel anti-HCMV agents targeting the UL89 terminase protein

发现和开发针对 UL89 终止酶蛋白的新型抗 HCMV 药物

基本信息

批准号：
10318943
负责人：
Robert James Geraghty
金额：
$ 65.45万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-25 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10318943
关键词：
ATP phosphohydrolase Acquired Immunodeficiency Syndrome Active Sites Antiviral Agents Binding Biochemical Biochemistry Biological Assay Brain Injuries Cell Culture Techniques Cell Survival Chemistry Cidofovir Clinic Collaborations Complex Crystallization Cytomegalovirus DNA Packaging Data Development Disease Drug Kinetics Drug Targeting Drug resistance Enzymes FDA approved Fetal Development Foscarnet Foundations Ganciclovir Generations Goals Human Immunocompromised Host In Vitro Individual Infection Infectious Agent Intervention Investigation Libraries Metals Molecular Target Morbidity - disease rate Mutation Mutation Analysis Newborn Infant Patients Pharmaceutical Chemistry Pharmaceutical Preparations Polymerase Prodrugs Production Property Prophylactic treatment Proteins Publishing Research Resistance Role Signal Transduction Structure Techniques Toxic effect Transplant Recipients Transplantation United States Food and Drug Administration Valganciclovir Viral Viral Genome Virus Virus Assembly Virus Replication Work allograft rejection analog base cost drug candidate endonuclease experimental study hearing impairment high throughput screening immune system function improved in vivo inhibitor innovation interdisciplinary approach mortality new therapeutic target novel novel therapeutics pharmacophore post-transplant pre-clinical prevent resistant strain scaffold screening side effect small molecule standard of care structural biology success targeted agent terminase tool viral genomics viral resistance virology virtual screening

项目摘要

Project Summary/Abstract Human cytomegalovirus (HCMV) infection in individuals lacking a fully functioning immune system, such as newborns and transplant patients, can result in severe and debilitating consequences. The majority of the US Food and Drug Administration approved anti-HCMV drugs target the viral polymerase and resistance to those drugs has appeared. Therefore, anti-HCMV drugs from novel targets are needed for use in combination with, or instead of, current polymerase inhibitors. The long-term goal of this proposal is to develop structurally novel direct-acting antivirals against HCMV targeting aspects of virus replication outside of those for currently approved drugs. Towards this end, a viral ATPase/endonuclease (pUL89) critically involved in viral genome packaging and virus assembly has been chosen as a target for antiviral intervention. The objective of this investigation is to identify, optimize and characterize pUL89 inhibitor scaffolds. To accomplish these goals, the following specific aims will be pursued: 1. Develop and implement screening assays to identify pUL89 and HCMV inhibitors. These assays include biochemical assays for pUL89 function as well as HCMV replication assays in cell culture. 2. HCMV pUL89 inhibitor hit generation and optimization. Hit generation will center around the focused screening of in-house synthetic small molecules and select compound libraries. Confirmed hits will be optimized via analogue synthesis, iterative SAR and in vitro ADME assays to generate potent inhibitors with favorable physicochemical properties. 3. Characterization of advanced inhibitors using virological, structural and pharmacokinetic techniques. Optimized inhibitor binding to pUL89 will be analyzed and refined using structural studies. Detailed virological experiments will be performed to characterize the mechanism of action, verify the target of these inhibitors and document their ability to work with current FDA approved drugs and against resistant virus. In addition, in vivo pharmacokinetic parameters of the optimized inhibitors will be determined and used to improve drug-like properties. At the conclusion of the studies outlined in this proposal, a better understanding of the mechanism of action and role of pUL89 endonuclease activity in virus replication will be gained and multiple potent preclinical drug candidates targeting pUL89 will be developed.

项目摘要/摘要缺乏功能齐全的免疫系统的个体中的人类巨细胞病毒（HCMV）感染，例如新生儿和移植患者可能会导致严重和衰弱的后果。美国大多数食品药品监督管理局批准的抗HCMV药物针对病毒聚合酶和耐药性药物已经出现。因此，需要使用新靶标的抗HCMV药物与或者不是当前的聚合酶抑制剂。该提议的长期目标是开发结构新颖直接作用抗病毒药，以针对HCMV靶向病毒复制方面的抗病毒药，目前批准的药物。为此，病毒式ATPase/核心酸酶（PUL89）严格参与病毒基因组包装和病毒组装已被选为抗病毒干预的靶标。这个目的研究是为了识别，优化和表征PUL89抑制剂支架。为了实现这些目标，将追求以下具体目标：1。开发和实施筛选分析以识别PUL89和 HCMV抑制剂。这些测定包括PUL89功能的生化测定以及HCMV复制细胞培养的测定。 2。HCMVPUL89抑制剂HIT生成和优化。命中一代将集中围绕着内部合成小分子和精选化合物库的集中筛选。确认的命中将通过模拟合成，迭代SAR和体外ADME分析进行优化具有良好物理化学特性的有效抑制剂。 3。使用高级抑制剂的表征病毒学，结构和药代动力学技术。将分析优化的抑制剂与PUL89的结合并使用结构研究进行了完善。将进行详细的病毒学实验以表征作用机理，验证这些抑制剂的目标并记录其与当前FDA合作的能力批准的药物和抗性病毒。另外，优化的体内药代动力学参数抑制剂将被确定并用于改善类似药物的特性。在概述的研究结束时在此提案中，更好地理解了pul89核酸内切酶活性的作用机理和作用在病毒中，将获得复制，并且针对PUL89的多个有效的临床前候选药物将是发达。