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

• 批准号: 10534193
• 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
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-25 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534193
• 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; Cytomegalovirus; Cytomegalovirus Infections; 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; 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; 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

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.

项目总结/文摘

项目成果

Repurposing N-hydroxy thienopyrimidine-2,4-diones (HtPD) as inhibitors of human cytomegalovirus pUL89 endonuclease: Synthesis and biological characterization.

• DOI: 10.1016/j.bioorg.2022.106198
• 发表时间: 2022-12
• 期刊: Bioorganic chemistry
• 影响因子: 5.1
• 作者: He T;Edwards TC;Majima R;Jung E;Kankanala J;Xie J;Geraghty RJ;Wang Z
• 通讯作者: Wang Z

Discovery of N-benzyl hydroxypyridone carboxamides as a novel and potent antiviral chemotype against human cytomegalovirus (HCMV).

• DOI: 10.1016/j.apsb.2021.08.019
• 发表时间: 2022-04
• 期刊: ACTA PHARMACEUTICA SINICA B
• 影响因子: 14.5
• 作者: Senaweera, Sameera;Edwards, Tiffany C.;Kankanala, Jayakanth;Wang, Yan;Sahani, Rajkumar Lalji;Xie, Jiashu;Geraghty, Robert J.;Wang, Zhengqiang
• 通讯作者: Wang, Zhengqiang

8-Hydroxy-1,6-naphthyridine-7-carboxamides as Inhibitors of Human Cytomegalovirus pUL89 Endonuclease.

8-羟基-1,6-萘吡啶-7-羧酰胺作为人类巨细胞病毒PUL89核酸内切酶的抑制剂。

• DOI: 10.1002/cmdc.202200334
• 发表时间: 2022-09-05
• 期刊: CHEMMEDCHEM
• 影响因子: 3.4
• 作者: Jung, Eunkyung;Majima, Ryuichi;Edwards, Tiffany C.;Soto-Acosta, Ruben;Geraghty, Robert J.;Wang, Zhengqiang
• 通讯作者: Wang, Zhengqiang