INHIBITORS OF SUBSTRATE ACTIVATED PROTEASES

底物活化蛋白酶抑制剂

基本信息

批准号：
6526106
负责人：
DANIEL H RICH
金额：
$ 22.33万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-09-01 至 2003-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6526106
关键词：
allosteric site botulinum toxins chemical synthesis combinatorial chemistry enzyme activity enzyme substrate enzyme substrate complex metalloendopeptidases peptide analog peptide chemical synthesis protease inhibitor tetanus toxin

项目摘要

DESCRIPTION (Verbatim from applicant's abstract): This is a medicinal chemistry proposal designed to develop new methods for inhibiting an important class of protease, those that are allosterically activated by substrate. Inhibitors of the botulinum toxin metalloproteases will be designed and synthesized based on two approaches: 1. design and synthesis of peptidyl transition-state analog inhibitors; and 2. Design based on the geometry of the zinc binding domain in the X-ray crystal structure of Botulinum toxin A. Botulinum toxin (BoNT) and tetanus toxin (TeNT) are converted in vivo to zinc metalloproteases which cleave single amide bonds in VAMP/synaptobrevin, SNAP25 and syntaxin. These metallo-proteases are the most selective proteases yet identified. Structure-activity data obtained with peptide substrates have established that substrate converts the BoNT metalloproteases from an inactive form to an active form. Examination of the 3.1 A X-ray crystal structure of native BoNT/A toxin provides insights into this unique substrate selectivity and also suggests how novel structures can be designed that will bind tightly to the INACTIVE protease, thereby preventing proteolysis. We postulate that it should be possible to stabilize the inactive form of the various BoNT metalloproteases; these inhibitors would be expected to have unique specificities and should not inhibit endogenous mammalian proteases. This new approach to the design of novel protease inhibitors will be applicable to other substrate activated proteases, many of which function in human biology and are implicated in disease.

描述（逐字研究来自申请人的摘要）：这是一种药物化学旨在开发新方法来抑制重要类别的提案蛋白酶，那些被底物变构激活的蛋白酶。抑制剂肉毒杆菌毒素金属蛋白酶将根据两种方法：1。肽基过渡态类似物的设计和合成抑制剂；和2。基于锌结合域的几何形状的设计肉毒杆菌毒素A.肉毒杆菌毒素（BONT）的X射线晶体结构和破伤风毒素（帐篷）在体内转换为锌金属蛋白酶在vamp/stynaptobrevin，snap25和语法中切割单酰胺键。这些金属 - 蛋白酶是尚未确定的最选择性的蛋白酶。用肽底物获得的结构活性数据已经确定底物将BONT金属蛋白酶从非活动形式转换为活动形式。检查3.1天然BONT/A毒素的X射线晶体结构提供有关这种独特的底物选择性的见解，也暗示了如何可以设计新颖的结构，将紧密结合到无活性蛋白酶，从而防止蛋白水解。我们假设应该是可以稳定各种BONT金属蛋白酶的非活性形式；这些抑制剂有望具有独特的特异性，不应抑制内源性哺乳动物蛋白酶。这种设计的新方法新型蛋白酶抑制剂将适用于其他底物激活蛋白酶，其中许多在人类生物学中起作用，并与疾病。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Design and synthesis of substrate-based inhibitors of botulinum neurotoxin type B metalloprotease.

B 型肉毒杆菌神经毒素金属蛋白酶底物抑制剂的设计和合成。

DOI：
10.1002/bip.10590
发表时间：
2003
期刊：
Biopolymers.
影响因子：
0
作者：
Oost,Thorsten;Sukonpan,Chanokporn;Brewer,Matthias;Goodnough,Michael;Tepp,William;Johnson,EricA;Rich,DanielH
通讯作者：
Rich,DanielH

Sequencing hydroxyethylamine-containing peptides via Edman degradation.

通过 Edman 降解对含羟乙胺的肽进行测序。

DOI：
10.1021/ol026590i
发表时间：
2002
期刊：
Organic letters
影响因子：
5.2
作者：
Brewer,Matthias;Oost,Thorsten;Sukonpan,Chanokporn;Pereckas,Michaela;Rich,DanielH
通讯作者：
Rich,DanielH

Synthesis of a tripeptide derivative containing the gln-arg hydroxyethylene dipeptide isostere.

含有gln-arg羟基乙烯二肽电子等排体的三肽衍生物的合成。