Study of gamma interferon agonists/mimetics

γ干扰素激动剂/模拟物的研究

• 批准号: 7568248
• 负责人: HOWARD M JOHNSON
• 金额: $ 39.91万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7568248
• 关键词: Agonist; Antiviral Agents; CD4 Positive T Lymphocytes; Cells; Communicable Diseases; Cytokine Inducible SH2-Containing Protein; Cytotoxic T-Lymphocytes; Exhibits; Helper-Inducer T-Lymphocyte; IL4 gene; Immune system; Immunity; Infection; Interferon Type II; Interferons; Interleukin-4; Macrophage Activation; Malignant Neoplasms; Mediation; Mouse Pox Virus; Mus; Natural Immunity; Natural Killer Cells; Oral Administration; Peptides; Pharmaceutical Preparations; Poxviridae; Poxviridae Infections; Proteins; Public Health; Relative (related person); Smallpox; Vaccinia; Vaccinia virus; Viral; Virus; Virus Diseases; cytokine; immune function; intraperitoneal; member; mimetics; novel; novel therapeutics; response; small molecule

DESCRIPTION (provided by applicant): Gamma interferon (IFN3) is an essential cytokine for mediation of immune functions that are critical for surveillance against infections and cancer. Important aspects of innate immunity, adaptive immunity, macrophage activation, natural killer cell activity, helper T cell responses, as well as cytotoxic T cell responses are all critically modulated by IFN3. We have developed small peptide mimetics of IFN3. The IFN3 mimetics exhibit antiviral activity against a variety of viruses including amelioration of the lethal effects of the poxvirus vaccinia in mice under conditions where intact IFN3 is ineffective because of anti- IFN proteins produced by poxviruses. The activating effects of IFN3 are suppressed by proteins called suppressors of cytokine signaling (SOCS), of which SOCS-1 is an important member. We have developed a small molecule SOCS-1 antagonist. In this renewal, we propose to study the interaction between IFN3, IFN3 mimetics, and SOCS-1 antagonist as per AIMs below to positively regulate the IFN responses of cells of the immune system and enhancement of protection of mice against vaccinia and ectromelia viruses with a view toward an IFN and SOCS-1 antagonist drug against smallpox. We hypothesize that our small peptide IFN mimetics and SOSC-1 antagonist represent novel antivirals against lethal poxvirus infections. 1. Protection of mice against lethal vaccinia virus infections by IFN mimetics. Effect of SOCS-1 antagonist on protection. 2. Compare intraperitoneal versus oral administration of IFN mimetic peptides for their relative ability to protect mice against lethal vaccinia virus infection. Effect of SOCS-1 antagonist. 3. Protection of mice against lethal ectromelia virus infection by IFN mimetics and SOCS-1 antagonist. 4. Protection of mice against superlethal ectromelia virus encoding the interleukin-4 (IL-4) gene by IFN mimetics and SOCS-1 antagonist. 5. Determine immunological aspects of treatment of mice with IFN mimetics. Effect of SOCS-1 antagonist. PUBLIC HEALTH RELEVENCE: Our interferon mimetic is a novel therapeutic for treating viral and other infectious diseases. The SOCS-1 antagonist should provide a new paradigm to boosting the immune system against infections and cancer.

描述(申请人提供)：伽玛干扰素(IFN3)是调节免疫功能的一种基本细胞因子，免疫功能对监测感染和癌症至关重要。天然免疫、获得性免疫、巨噬细胞激活、自然杀伤细胞活性、辅助性T细胞反应以及细胞毒性T细胞反应的重要方面都受到IFN3的关键调控。我们已经开发了IFN3的小肽模拟物。IFN3模拟物显示出对多种病毒的抗病毒活性，包括在完整的IFN3由于痘病毒产生的抗干扰素蛋白而无效的条件下，改善痘病毒痘苗对小鼠的致死作用。IFN3的激活作用被称为细胞因子信号转导抑制因子(SOCS)的蛋白质所抑制，SOCS-1是其中的重要成员。我们开发了一种小分子SOCS-1拮抗剂。在这次更新中，我们建议研究IFN3、IFN3类似物和SOCS-1拮抗剂之间的相互作用，目的是积极调节免疫系统细胞的干扰素反应，增强小鼠对牛痘和皮疹病毒的保护，以期开发出一种干扰素和SOCS-1拮抗剂来治疗天花。我们假设我们的小肽干扰素模拟物和SOSC-1拮抗剂代表了针对致死性痘病毒感染的新型抗病毒药物。1.用干扰素模拟物保护小鼠免受致死性痘苗病毒感染。SOCS-1拮抗剂的保护作用。2.比较腹腔注射和口服干扰素模拟肽对小鼠免受致死性痘苗病毒感染的相对保护能力。SOCS-1拮抗剂的作用。3.干扰素模拟物和SOCS-1拮抗剂对小鼠致死性蜕皮病病毒感染的保护作用。4.干扰素模拟物和SOCS-1拮抗剂对编码IL-4基因的超致死性蜕皮病病毒的保护作用。5.确定干扰素模拟物治疗小鼠的免疫学方面。SOCS-1拮抗剂的作用。公共卫生报道：我们的干扰素模拟物是一种治疗病毒和其他传染病的新疗法。SOCS-1拮抗剂应该提供一种新的范例来增强免疫系统对抗感染和癌症。