Study of gamma interferon agonists/mimetics

描述（由申请人提供）：γ干扰素（IFN3）是一种重要的细胞因子，介导免疫功能，对监测感染和癌症至关重要。先天免疫、适应性免疫、巨噬细胞活化、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的关键调节。我们已经开发了IFN3的小肽模拟物。在完整的IFN3由于痘病毒产生的抗IFN蛋白而无效的情况下，IFN3模拟物对多种病毒表现出抗病毒活性，包括改善痘病毒痘苗在小鼠中的致死效应。IFN3的激活作用被称为细胞因子信号抑制因子（SOCS）的蛋白质抑制，其中SOCS-1是一个重要成员。我们开发了一种小分子SOCS-1拮抗剂。在本论文中，我们建议研究IFN3、IFN3模拟物和SOCS-1拮抗剂之间的相互作用，以积极调节免疫系统细胞的IFN反应，增强小鼠对牛痘和羊痘病毒的保护作用，以期开发一种IFN和SOCS-1拮抗剂治疗天花。我们假设我们的小肽IFN模拟物和SOSC-1拮抗剂代表了对抗致命痘病毒感染的新型抗病毒药物。1. 干扰素模拟物对小鼠抗致死性牛痘病毒感染的保护作用。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保护小鼠免受致命痘苗病毒感染的相对能力。SOCS-1拮抗剂的作用。3. IFN模拟物和SOCS-1拮抗剂对小鼠致死性羊爪病毒感染的保护作用。4. IFN模拟物和SOCS-1拮抗剂对编码白细胞介素-4 （IL-4）基因的超致死性鼠肺病毒的保护作用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。公共卫生相关性：我们的干扰素模拟物是一种治疗病毒性疾病和其他感染性疾病的新疗法。SOCS-1拮抗剂应该为增强免疫系统抗感染和癌症提供一个新的范例。

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.