Hexameric PBGS as a Bioterrorism Defense

六聚 PBGS 作为生物恐怖主义防御手段

基本信息

批准号：
6853243
负责人：
EILEEN K JAFFE
金额：
$ 33.85万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2007-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6853243
关键词：
Pseudomonas aeruginosa allosteric site antiinfective agents biochemistry biohazard detection bioterrorism /chemical warfare computer simulation drug design /synthesis /production enzyme activity enzyme biosynthesis enzyme model metalloenzyme model design /development molecular biology polymerase chain reaction porphobilinogen synthase protein structure tetrapyrroles

项目摘要

DESCRIPTION (provided by applicant): National defense requires development of novel strategies to combat potential bio-terrorism agents. One target of this strategy is the development of new antimicrobial agents. The Jaffe laboratory has identified a hexamer-octamer equilibrium as the structural basis for allosteric control of a key enzyme in tetrapyrrole biosynthesis, porphobilinogen synthase (PBGS). Trapping of the inactive hexamer is proposed as a basis for discovery of new antimicrobials directed against the NIAID priority pathogens Burkholderia pseudomallei, Brucella mefitensis, Burkholderia mallei, Rickettsia prowazekii, Vibrio cholerae, and Yersinia enterocolitica. The aims of this exploratory proposal are: 1) To build protein structure models for hexamers of PBGS from these pathogens; 2) To use computational docking procedures to discover molecules that will preferentially bind to and stabilize the hexamer; and 3) To test the identified molecules for their ability to inhibit the PBGS of these pathogens while not inhibiting human PBGS. The current proposal describes a high risk - high impact exploratory project. Success of the proposed studies will establish a much needed new target for species selective antibiotic development that can be applied to bio-defense against NIAID priority pathogens.

描述（由申请人提供）：国防需要制定新的战略来打击潜在的生物恐怖分子。这一战略的目标之一是开发新的抗菌药物。 Jaffe 实验室已确定六聚体-八聚体平衡作为四吡咯生物合成中关键酶胆色素原合酶 (PBGS) 变构控制的结构基础。捕获无活性的六聚体被提议作为发现针对 NIAID 优先病原体拟鼻疽伯克霍尔德氏菌、美菲特布鲁氏菌、鼻疽伯克霍尔德氏菌、普瓦泽基立克次体、霍乱弧菌和小肠结肠炎耶尔森氏菌的新型抗菌药物的基础。该探索性提案的目的是：1）建立来自这些病原体的 PBGS 六聚体的蛋白质结构模型； 2) 使用计算对接程序来发现优先结合并稳定六聚体的分子； 3) 测试已鉴定的分子抑制这些病原体的 PBGS 同时不抑制人类 PBGS 的能力。目前的提案描述了一个高风险、高影响的探索性项目。拟议研究的成功将为物种选择性抗生素开发建立一个急需的新目标，可应用于针对 NIAID 优先病原体的生物防御。