Granulysin Derived Immunotherapeutics for Biodefense

描述（由申请人提供）：防御与在恐怖主义或战争行为中使用生物制剂有关的感染是国家优先事项。为了实现这一目标，必须开发新的方法来检测，治疗和预防A-C类病原体的感染。治疗可能包括在直接威胁的情况下预防感染，保护免疫功能低下的个体，或暴露后治疗以抑制感染和疾病。用于这些应用的理想试剂将是稳定的、广谱的、快速作用的、对人类细胞无毒的、便宜的并且易于制造。常规抗生素符合其中一些标准，但抗生素耐药性生物体的增加和新的广谱抗生素的缺乏使得鉴定新的抗菌剂势在必行。颗粒溶素是由人自然杀伤细胞和活化的T淋巴细胞表达的α-螺旋蛋白。重组颗粒溶解素溶解哺乳动物细胞和广谱微生物。合成肽（10-30个残基）对应于颗粒溶素的中心区域概括了其溶解活性。在这些肽的一个子集中，半胱氨酸或精氨酸残基的替换，或引入D-氨基酸以破坏α-螺旋，导致对哺乳动物细胞的活性丧失，而对抗微生物活性几乎没有影响或没有影响。该计划的目标是开发基于这些颗粒溶素肽的新型免疫治疗剂。将在项目1中生成其他衍生物，在项目2中进行体外和体内评价，并在项目3中表征作用机制。这些项目将得到三个核心的支助-综合/清查; BSL-3设施和行政管理。从这些研究中收集到的信息应该会导致新的免疫治疗药物的开发，用于生物防御和治疗抗生素耐药病原体。

DESCRIPTION (provided by applicant): Defense against infections related to the use of biological agents in acts of terrorism or war is a national priority. To achieve this end, new methods to detect, treat, and prevent infection with Category A-C pathogens must be developed. Treatment may include prevention of infection in the case of an immediate threat, protection of immunocompromised individuals, or post-exposure treatment to suppress infection and disease. Ideal agents for these applications would be stable, broad spectrum, fast acting, nontoxic towards human cells, inexpensive, and easy to manufacture. Conventional antibiotics meet some of these criteria, but both the rise in antibiotic resistant organisms and a dearth of new broad-based antibiotics make identification of new antimicrobials imperative. Granulysin is an alpha-helical protein expressed by human natural killer cells and activated T lymphocytes. Recombinant granulysin lyses both mammalian cells and a broad spectrum of microbes. Synthetic peptides (10-30 residues) corresponding to the central region of granulysin recapitulate its lytic activity. In a subset of these peptides, replacement of cysteine or arginine residues, or introduction of D-amino acids to disrupt the alpha-helix, results in the loss of activity against mammalian cells with little or no effect on antimicrobial activity. The goal of this Program is to develop novel immunotherapeutics based on these granulysin peptides. Additional derivatives will be generated in Project 1, evaluated in vitro and in vivo in Project 2, and characterized for mechanism of action in Project 3. These projects will be supported by three cores--synthesis/inventory; a BSL-3 facility, and administration. The information gleaned from these studies should lead to the development of new immunotherapeutics for biodefense and for treatment of antibiotic resistant pathogens.