Novel Interferons and small molecule enhancers of the interferon pathway

新型干扰素和干扰素途径的小分子增强剂

基本信息

批准号：
8643869
负责人：
Kenan Christopher GARCIA
金额：
$ 48.43万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-10 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8643869
关键词：
Adverse effects Affect Affinity Aftercare Anabolism Antiviral Agents Antiviral Response Biochemical Biological Biological Assay Biological Factors Biology Cells Chemicals Chemistry Chronic Clinic Clinical Collaborations Combined Modality Therapy Complement Complex Cytokine Receptors Cytometry Dendritic Cells Dengue Virus Development Dimerization Dose Engineering Enhancers Evaluation Evolution Exhibits Gene Cluster Genes Genetic Transcription Genotype Geometry Goals Hepatitis C Hepatitis C virus Hepatitis C-Like Viruses Immune Immune response Immunity In Vitro Infection Interferon Receptor Interferon Type I Interferon-alpha Interferons Kinetics Link Luciferases MHC Class I Genes Macrophage Activation Measures Mediating Methods Metric Modification Molecular Morbidity - disease rate Natural Killer Cells Organism Outcome Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phosphorylation Production Property Protein Engineering Proteins RNA Viruses Recombinant Proteins Regimen Relative (related person)Reporter Resistance Ribonucleases Rice Signal Transduction Specificity Streptomyces Structure Structure-Activity Relationship System Testing Therapeutic Time Toxic effect Variant Viral Viral Physiology Virus Virus Diseases West Nile virus Work Yellow Fever analog base biophysical properties combinatorial cytokine design directed evolution extracellular improved in vitro Assay inhibitor/antagonist innovation insight interest interferon therapy meetings novel pathogen phosphoric diester hydrolase prevent receptor receptor binding response screening small molecule standard of care success

项目摘要

Production of IFNa is one of the earliest host immune responses after viral infection. The fundamental importance of this Type I interferon, lies in its ability to induce downstream activation of both innate and adaptive immune cells via direct and indirect mechanisms. Because they promote potent anti-viral activity, Type I IFNs have been used as both a monotherapy and in combination with other small molecules for enhanced efficacy in the treatment of chronic viral infections, such as Hepatitis C. Despite the fact that only a portion of patients respond to treatment, and that adverse side-effects from long term dosing regimens are a significant barrier, IFNs remain the best standard of care. Thus, it is the overall goal of this project to develop, in parallel, two classes of IFNa enhancers, one protein and the other small molecule, that may be used alone or in combination with other therapeutics for the broad-spectrum treatment of viral infections. First, in an effort to improve functional responses to IFNs and reduce their toxicity, the Garcia group has developed an approach to re-engineer and expand the menu of existing IFNs with recombinant proteins that exhibit superior therapeutic properties. This method, known as in vitro evolution, has been previously and successfully employed by the Garcia group to engineer cytokines with unique structure-activity relationships and that have proven to be more efficacious than the natural cytokine. Second, the Khosia group will pursue chemical biological studies on a recently discovered polyketide natural product, A-74528, that has been found to enhance the antirviral effects of IFNa. The Khosia group will also engage in production and biochemical and structural analysis of A-74528 analogs. In Aim 1 we will engineer and improve IFN antiviral activities using in vitro evolution to create IFNs with altered affinity or dimerization geometries with the receptor complex. In Aim 2 we will conduct biophysical studies of candidate IFNs to determine their mechanisms of action, as monotherapies or in combination with other therapeutics. In Aim 3 we will investigate the inhibitory mechanism and pharmacological properties of A- 74528 through kinetic and dose-response analyses. In Aim 4 we will design and synthesize analogs of A- 74528 to define structure activity relationships. This unique interfacing of protein and small molecule medicinal chemistry will hopefully yield highly granular, predictive structure-activity metrics linking the molecular and mechanistic parameters of IFN action to antiviral function.

IFNa的产生是病毒感染后最早的宿主免疫反应之一。这种 I 型干扰素的根本重要性在于它能够通过直接和间接机制诱导先天性和适应性免疫细胞的下游激活。由于 I 型干扰素可促进有效的抗病毒活性，因此它们既可用作单一疗法，也可与其他小分子联合使用，以增强治疗丙型肝炎等慢性病毒感染的疗效。尽管患者对治疗有反应，并且长期给药方案的不良副作用是一个重大障碍，但干扰素仍然是最佳的治疗标准。因此，该项目的总体目标是并行开发两类 IFNa 增强剂，一种是蛋白质，另一种是小分子，它们可以单独使用或与其他疗法联合使用，以广谱治疗病毒感染。首先，为了改善对 IFN 的功能反应并降低其毒性，Garcia 小组开发了一种方法，利用表现出卓越治疗特性的重组蛋白重新设计和扩展现有 IFN 的菜单。这种被称为体外进化的方法之前已被 Garcia 小组成功地用于设计具有独特结构-活性关系的细胞因子，并且已被证明比天然细胞因子更有效。其次，Khosia 小组将对最近发现的聚酮天然产物 A-74528 进行化学生物学研究，该产物被发现可以增强 IFNa 的抗病毒作用。 Khosia 集团还将从事 A-74528 类似物的生产以及生化和结构分析。在目标 1 中，我们将利用体外进化来设计和改进 IFN 抗病毒活性，以产生与受体复合物具有改变的亲和力或二聚化几何形状的 IFN。在目标 2 中，我们将对候选干扰素进行生物物理学研究，以确定其作为单一疗法或与其他疗法组合的作用机制。在目标 3 中，我们将通过动力学和剂量反应分析来研究 A-74528 的抑制机制和药理学特性。在目标 4 中，我们将设计和合成 A-74528 的类似物来定义结构活性关系。蛋白质和小分子药物化学的这种独特的界面将有望产生高度精细的、预测性的结构活性指标，将 IFN 作用的分子和机制参数与抗病毒功能联系起来。