Genetic Pathways of Human Cytomegalovirus Drug Resistance

人类巨细胞病毒耐药性的遗传途径

基本信息

批准号：
9115029
负责人：
Sunwen Chou
金额：
$ 31.5万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9115029
关键词：
Alternative Therapies Antiviral Agents Antiviral Therapy Binding Binding Sites Cells Chromosome Mapping Cidofovir Clinical Clinical Trials Complex Cytomegalovirus DNA DNA Polymerase Inhibitor DNA biosynthesis DNA-Directed DNA Polymerase Data Development Diagnosis Disease Drug Exposure Drug resistance Drug resistance pathway Equilibrium Evolution Exonuclease Exposure to Figs - dietary Formulation Foscarnet Ganciclovir Genes Genetic Genetic Polymorphism Genotype Growth Human Hypersensitivity Immunocompromised Host In Vitro Laboratories Licensing Malignant Neoplasms Mediating Mission Molecular Morphologic artifacts Mutagenesis Mutation Oral Pathway interactions Pattern Pharmaceutical Preparations Phase Phenotype Phosphotransferases Polymerase Polymerase Gene Positioning Attribute Prodrugs Recombinants Reporter Genes Research Resistance Resistance profile Structure System Technology Therapeutic Toxic effect Transplant Recipients Valganciclovir Viral base cost design drug candidate fitness genetic resistance improved in vivo inhibitor/antagonist kinase inhibitor maribavir mutant next generation sequencing novel therapeutics nucleoside analog protein expression public health relevance resistance mechanism resistance mutation terminase viral DNA

Alternative Therapies Antiviral Agents Antiviral Therapy Binding Binding Sites Cells Chromosome Mapping Cidofovir Clinical Clinical Trials Complex Cytomegalovirus DNA DNA Polymerase Inhibitor DNA biosynthesis DNA-Directed DNA Polymerase Data Development Diagnosis Disease Drug Exposure Drug resistance Drug resistance pathway Equilibrium Evolution Exonuclease Exposure to Figs - dietary Formulation Foscarnet Ganciclovir Genes Genetic Genetic Polymorphism Genotype Growth Human Hypersensitivity Immunocompromised Host In Vitro Laboratories Licensing Malignant Neoplasms Mediating Mission Molecular Morphologic artifacts Mutagenesis Mutation Oral Pathway interactions Pattern Pharmaceutical Preparations Phase Phenotype Phosphotransferases Polymerase Polymerase Gene Positioning Attribute Prodrugs Recombinants Reporter Genes Research Resistance Resistance profile Structure System Technology Therapeutic Toxic effect Transplant Recipients Valganciclovir Viral base cost design drug candidate fitness genetic resistance improved in vivo inhibitor/antagonist kinase inhibitor maribavir mutant next generation sequencing novel therapeutics nucleoside analog protein expression public health relevance resistance mechanism resistance mutation terminase viral DNA

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项目摘要

DESCRIPTION (provided by applicant): Toxicity and drug resistance limit the efficacy of antiviral therapy for cytomegalovirus (CMV) disease in immunosuppressed hosts such as cancer and transplant recipients. The basic objective of this research is to characterize the viral mutations and associated mechanisms of resistance to anti-CMV drugs in clinical use, in order to improve the genotypic diagnosis of CMV drug resistance and the selection and development of alternate therapies. For currently licensed drugs (ganciclovir, foscarnet and cidofovir), many resistance mutations and polymorphisms in the CMV UL97 kinase and UL54 DNA polymerase genes have been and continue to be identified and phenotyped, sometimes as mixed subpopulations. Clinical trials of new anti-CMV drugs have recently accelerated, including the UL97 kinase inhibitor maribavir, the terminase inhibitor letermovir, and additional DNA polymerase inhibitors brincidofovir and cyclopropavir. Defining the genetics of resistance and cross-resistance among these compounds is an essential aspect of these new antiviral treatment options. Technical advances in genotyping and recombinant phenotyping are facilitating this research, including efficient mutagenesis of cloned baseline laboratory strains expressing reporter genes for viral quantitation, tagged protein expression systems and next-generation sequencing technology. Specific aims are (1) define the evolution and phenotypes of CMV mutations that develop after in vitro or in vivo exposure to antiviral compounds; (2) elucidate mechanisms of DNA chain extension by which the same exonuclease mutations can confer resistance to some polymerase inhibitors but hypersensitivity to others, and (3) characterize the genetic pathways of resistance to terminase inhibitors with emphasis on mutations in a region of the UL56 gene that confer high-level letermovir resistance.

描述（应用程序提供）：毒性和耐药性限制了抗病毒治疗对免疫抑制宿主（例如癌症和移植受者）巨细胞病毒（CMV）疾病的有效性。这项研究的基本目的是表征病毒为了改善CMV耐药性的基因型诊断以及替代疗法的选择和发展，对抗CMV药物的抗性的突变和相关机制。对于目前有执照的药物（Ganciclovir，Foscarnet和Cidofovir），CMV UL97激酶和UL54 DNA聚合酶基因中的许多抗性突变和多态性已经被鉴定并继续被鉴定，有时是混合的子群。新抗CMV药物的临床试验最近加速了，包括UL97激酶抑制剂MARIVIV，末端酶抑制剂LETEROMOVIR以及其他DNA聚合酶抑制剂Brincidofofovir和Cyclopopavir。在这些化合物中定义耐药性和抗性的遗传学是这些新的抗病毒治疗选择的重要方面。基因分型和重组表型的技术进步支持这项研究，包括有效的克隆基线实验室菌株的诱变表达了用于病毒定量，标记的蛋白质表达系统和下一代测序技术的报告报告基因。具体目的是（1）定义在体外或体内暴露于抗病毒化合物后发展的CMV突变的演化和表型；（2）阐明DNA链扩展的机制，通过这些机制，相同的核酸酶突变可以赋予某些聚合酶抑制剂但对其他聚合酶抑制作用过敏，并且（3）表征对末端酶抑制剂的遗传途径的遗传途径，并强调UL56 Gene Eull56 Gene Enferene High-evel Fitermevel litemevel tem vellevel tevel litemevel litevel litemevel litemevel tevel litemevel consivemevel litemevel consiveme contractiation。