DEVELOPMENT OF AN ANTI-SEPSIS THERAPEUTIC

抗脓毒症治疗药物的开发

• 批准号: 2776848
• 负责人: Frederick S Hagen
• 金额: $ 15.02万
• 依托单位: ICOGENEX CORPORATION
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-15 至 2000-03-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2776848
• 关键词: antisepsis; biochemical evolution; carboxylic ester hydrolases; complementary DNA; drug design /synthesis /production; enzyme activity; lipopolysaccharides; molecular genetics; protein binding

The goal of this Phase I research is to demonstrate the feasibility of developing an anti-sepsis therapeutic. A half million Americans each year are afflicted with sepsis. Of this large number of people, nearly 40 percent or 200,000 people die of this syndrome. Molecular evolution will be used to evolved enhanced properties of acyloxyacyl hydrolase (AOAH), a natural human lysosomal enzyme that detoxifies lipopolysaccharide (LPS or endotoxin), the effector molecule of sepsis. The molecular evolution will increase the affinity of AOAH for LPS to enable it to effectively remove LPS from associating with mediators of sepsis. The major challenge in this investigation is the development of selective procedures that will effectively enrich for AOAH molecules with enhanced properties. Success in Phase I will lead to the isolation of greatly enhanced AOAH anti-sepsis agent in Phase II. Investigations in Phase II will involve in vitro validation of the anti-sepsis character of enhanced AOAH and assessment of the anti-sepsis properties in sepsis animal model systems. PROPOSED COMMERCIAL APPLICATION Sepsis is a major health care problem with half a million people in America contracting this disease each year causing 200,000 fatalities. With increased affinity to LPS (endotoxin) the triggering element in sepsis, acyloxyacyl hydrolase (AOAH), a human enzyme which detoxifies LPS, would have great utility as an anti-sepsis protein therapeutic.

该一期研究的目标是证明开发抗脓毒症治疗方法的可行性。 每年有 50 万美国人患有败血症。 在这一大群人中，近 40%（即 20 万人）死于这种综合症。 分子进化将用于进化酰氧酰基水解酶（AOAH）的增强特性，AOAH是一种天然的人类溶酶体酶，可以解毒脂多糖（LPS或内毒素），脓毒症的效应分子。 分子进化将增加 AOAH 对 LPS 的亲和力，使其能够有效去除 LPS 与脓毒症介质的结合。 这项研究的主要挑战是开发选择性程序，以有效富集具有增强特性的 AOAH 分子。 第一阶段的成功将导致在第二阶段分离出大大增强的 AOAH 抗败血症剂。 II 期研究将涉及增强型 AOAH 抗脓毒症特性的体外验证以及脓毒症动物模型系统中抗脓毒症特性的评估。拟议的商业应用脓毒症是一个主要的医疗保健问题，美国每年有 50 万人感染这种疾病，导致 20 万人死亡。 随着对脓毒症触发因素 LPS（内毒素）的亲和力增加，酰氧基酰基水解酶 (AOAH)（一种解毒 LPS 的人类酶）将作为抗脓毒症蛋白治疗剂具有巨大的实用性。

项目成果

Immune interaction between respiratory syncytial virus infection and allergen sensitization critically depends on timing of challenges.

• DOI: 10.1086/324429
• 发表时间: 2001-12
• 期刊: The Journal of infectious diseases
• 作者: R. Peebles;K. Hashimoto;R. Collins;K. Jarzecka;J. Furlong;D. Mitchell;J. Sheller;B. Graham