Novel Chemical and Immunological Approaches to Influenza Therapy

流感治疗的新化学和免疫学方法

• 批准号: 8076285
• 负责人: MICHAEL B OLDSTONE
• 金额: $ 163.57万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8076285
• 关键词: Aerosols; Affinity; Anatomy; Animal Model; Animals; Antigen-Presenting Cells; Antiviral Agents; Antiviral Therapy; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Chemicals; Clinical; Clonal Expansion; Contracts; Coupled; Data; Development; Dose; Drug Formulations; Epitopes; Event; Hand functions; Human; Immune response; Immunobiology; Immunologics; Immunology; Infection; Influenza; Influenza A Virus, H5N1 Subtype; Injury; Institutes; International; Label; Lung; Lymphocytic choriomeningitis virus; Molecular; Morbidity - disease rate; Mus; Pathogenicity; Pathology; Pharmaceutical Chemistry; Prophylactic treatment; Public Health; Pulmonary Edema; Recombinants; Research Project Grants; Role; Site; Sphingosine; Sphingosine-1-Phosphate Receptor; Survival Rate; T Virus; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Therapeutic; Toxic effect; Viral; Viral load measurement; Virulent; Virus; Virus Diseases; analog; anti-influenza; experience; flu; immunopathology; in vivo; influenzavirus; man; mortality; novel; novel vaccines; pandemic disease; pandemic influenza; prophylactic; recombinant virus; research study; response; scale up

DESCRIPTION (provided by applicant): Influenza virus remains a major public health concern for the USA and the world. To best insure that a pandemic like the 1918-1919 episode does not reoccur, national and international surveillance, effective vaccine and novel and effective antiviral therapy are required. Here we propose a multi-institute cooperative research project focused on discovery and use of novel chemicals that selectively manipulate the immunologic response in the lung as a therapeutic approach to better control influenza viral infection. We and others have evidence in animal models that the immune response (immunopathology) to influenza contributes significantly to morbidity and mortality. We have preliminary but impressive data that low doses of sphingosine analogs administered as a single dose intratracheally but not systemically acts locally in the lung to specifically suppress antiviral T cell proliferative responses. We propose that: 1) single aerosol exposure of the lungs to a sphingosine analog will inhibit antiviral proliferation thus modulating the resultant immunopathologic injury; 2) this mechanism will synergize with classic antiviral protective therapy; 3) combination of these therapeutic approaches will protect the host during H5N1 infection. To test this proposal Hugh Rosen, with expertise in immunology, medicinal chemistry and human therapeutics, will continue the development of sphingosine compounds and their testing with Michael Oldstone, experienced in viral-immunobiology and use of the WSN recombinant virus expressing immunodominant CDS and CD4 T cell epitopes of LCMV. WSN recombinant infection is preceded with transfer of GFP, RFP or Th1.1 congenically labeled CD4 and CDS T cells to these LCMV epitopes allowing quantitation of flu-specific T cells in the lung. The LCMV recombinant as well as GFP-labeled WSN virus used has been prepared by the third partner in this enterprise, Yoshihiro Kawaoka, an expert in influenza viruses. Kawaoka will test novel sphingosine analogs against H5N1 influenza virus.

描述（由申请人提供）：流感病毒仍然是美国和世界的主要公共卫生问题。为了最好地确保像1918-1919年那样的大流行不再发生，需要国家和国际监测、有效的疫苗和新颖有效的抗病毒治疗。在这里，我们提出了一个多机构合作研究项目，重点是发现和使用新的化学物质，选择性地操纵肺部的免疫反应作为一种治疗方法，以更好地控制流感病毒感染。 我们和其他人在动物模型中有证据表明，对流感的免疫反应（免疫病理学）对发病率和死亡率有显著影响。我们有初步的但令人印象深刻的数据，即低剂量的鞘氨醇类似物作为单次剂量在肺内给药，但不是全身性地在肺中局部作用，以特异性地抑制抗病毒T细胞增殖反应。我们建议：1）肺对鞘氨醇类似物的单次气溶胶暴露将抑制抗病毒增殖，从而调节所得的免疫病理损伤; 2）该机制将与经典的抗病毒保护性治疗协同作用; 3）这些治疗方法的组合将在H5 N1感染期间保护宿主。 为了测试这一提议，具有免疫学、药物化学和人类治疗学专业知识的Hugh罗森将继续开发鞘氨醇化合物，并与Michael Oldstone一起进行测试，Michael Oldstone在病毒免疫生物学和使用WSN重组病毒表达LCMV的免疫显性CDS和CD 4 T细胞表位方面经验丰富。WSN重组感染之前，将GFP、RFP或Th1.1同源标记的CD 4和CDS T细胞转移至这些LCMV表位，从而允许定量肺中的流感特异性T细胞。LCMV重组体以及GFP标记的WSN病毒是由该企业的第三个合作伙伴，流感病毒专家Yoshihiro Kawaoka制备的。Kawaoka将测试针对H5 N1流感病毒的新型鞘氨醇类似物。

项目成果

Discovery, synthesis and SAR analysis of novel selective small molecule S1P4-R agonists based on a (2Z,5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2-(alkylimino)thiazolidin-4-one chemotype.

• DOI: 10.1016/j.bmcl.2011.09.049
• 发表时间: 2011-11-15
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
• 影响因子: 2.7
• 作者: Urbano, Mariangela;Guerrero, Miguel;Velaparthi, Subash;Crisp, Melissa;Chase, Peter;Hodder, Peter;Schaeffer, Marie-Therese;Brown, Steven;Rosen, Hugh;Roberts, Edward
• 通讯作者: Roberts, Edward