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

• 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
• 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

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应答之一。这种I型干扰素的根本重要性在于其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活化的能力。因为它们促进有效的抗病毒活性，I型IFN已被用作单一疗法和与其他小分子组合用于增强治疗慢性病毒感染（如丙型肝炎）的功效。尽管只有一部分患者对治疗有反应，并且长期给药方案的不良副作用是一个重要的障碍，但IFN仍然是最好的护理标准。因此，该项目的总体目标是平行开发两类IFNa增强剂，一种蛋白质和另一种小分子，其可以单独使用或与其他治疗剂组合用于病毒感染的广谱治疗。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，用表现出上级治疗特性的重组蛋白质来重新设计和扩展现有IFN的菜单。这种方法被称为体外进化，以前已被Garcia小组成功地用于工程化具有独特结构-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，该天然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、生化和结构分析。在目标1中，我们将使用体外进化来设计和改进IFN抗病毒活性，以产生具有改变的亲和力或与受体复合物的二聚化几何结构的IFN。在目标2中，我们将对候选IFN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，以确定结构活性关系。蛋白质和小分子药物化学的这种独特的接口将有望产生高度颗粒化的，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。