Antibacterial methionine aminopeptidase inhibitors

抗菌蛋氨酸氨肽酶抑制剂

基本信息

批准号：
7270317
负责人：
QI-ZHUANG YE
金额：
$ 36.98万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2005-07-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7270317
关键词：
Antibacterial methionine aminopeptidase inhibitors

项目摘要

DESCRIPTION (provided by the applicant): All bacteria possess a single methionine aminopeptidase (MetAP) that is absolutely essential for cell survival. In contrast, eukaryotic cells express two MetAP enzymes and can survive if one of them is eliminated by genetics or inhibition. This enzyme is therefore a potentially attractive target for novel broad spectrum antibacterial compounds. This key enzyme catalyzes the removal of N-terminal methionine from newly synthesized proteins and requires a divalent metal ion such as Mn(ll), Fe(ll), Co(ll), Ni(ll) or Zn(ll) for activity. However, it is currently unclear which of these ions are the most important in vivo. Because most MetAP inhibitors have been discovered and characterized on the Co(ll) enzyme, they may not inhibit other metalloforms of MetAP. The objectives of this proposal are (1) to define the in vivo relevant metalloform of MetAP in E. coli and (2) to identify metalloform-selective MetAP inhibitors as both research tools and leads for drug development. We expect to obtain MetAP inhibitors that are highly selective for each of the relevant metalloforms. These unique inhibitors will be used to identify the in vivo metal utilized by MetAP in E. coli. The successful completion of this research will help to clarify the in vivo metal for MetAP and provide nonpeptidic MetAP inhibitors as leads for effective antibacterial agents to treat infectious diseases.

描述（由申请人提供）：所有细菌都具有单一蛋氨酸氨基肽酶（Metap），这对于细胞存活绝对必不可少。相反，真核细胞表达两种转移酶，如果其中一个被遗传学或抑制消除，则可以生存。因此，该酶是新型广谱抗菌化合物的潜在吸引靶标。该键酶催化从新合成的蛋白质中去除N末端蛋氨酸，并需要具有二价金属离子，例如Mn（LL），Fe（LL），CO（LL），Ni（LL），Ni（LL）或Zn（LL）（LL）。但是，目前尚不清楚这些离子中的哪一种是体内最重要的。由于在CO（LL）酶上已经发现并表征了大多数元抑制剂，因此它们可能不会抑制其他Metap的金属型。该提案的目标是（1）定义大肠杆菌和（2）中Metap的体内相关金属类型，以鉴定金属实型选择性元抑制剂作为研究工具和药物开发的铅。我们期望获得对每个相关金属类型的高度选择性的Metap抑制剂。这些独特的抑制剂将用于识别大肠杆菌中Metap使用的体内金属。这项研究的成功完成将有助于阐明用于转移的体内金属，并提供非肽元抑制剂，作为有效抗菌剂治疗传染病的铅。