HTS for selective inhibitors of Meprin alpha and beta

产品说明： 安眠药？然后呢？是与系统性硬化症有关的metzincin蛋白酶超家族的成员。研究表明，Meprin的过度表达？然后呢？与皮肤和其它器官和组织中纤维状胶原沉积的增加有关。这可能导致肾脏、肺和心脏纤维化，最终导致衰竭和死亡。 研究Meprin的主要障碍是什么？然后呢？在系统性硬化症中的作用是缺乏选择性抑制剂。大部分的安眠药？然后呢？迄今为止开发的抑制剂以靶向活性位点Zn的Zn结合部分为特征。有大约70种已知的人类金属蛋白酶在其活性位点具有Zn，这导致Zn结合抑制剂的脱靶毒性。 根据我们的初步结果，我们假设，Meprin？然后呢？选择性抑制剂将是有效的研究工具，在系统性硬化症，其中Meprin？然后呢？有牵连目前还没有公开的选择性抑制剂Meprin？然后呢？金属蛋白酶 该项目的总体目标是开发选择性抑制剂Meprin？然后呢？具体目标 本提案的重点是（1）由> 640，000化合物组成的Scripps库的HTS;（2）Meprin选择性探针的药物化学和体外表征？然后呢？ 我们的实验室是独特的定位，以实现这些目标，由于在生物学，生物化学和药物/金属蛋白酶的探针发现的专业知识。我们发现了一类新的金属蛋白酶ADAM 17抑制剂，其保留了最接近的类似物ADAM 10和最常见的抗靶标（MMP-14和-8）。据我们所知，我们是第一个报告具有这种独特选择性的ADAM 17抑制剂的实验室。此外，我们发现了新的选择性非锌结合抑制剂的另一种金属蛋白酶，MMP-13参与骨关节炎。与本提案最密切相关的是，这两项发现都是利用美国国立卫生研究院或TPIMS图书馆的HTS与斯克里普斯研究所分子筛选中心（由斯派塞博士和斯派塞先生共同领导）和菲尔兹博士密切合作取得的。我们坚信，Scripps库的HTS将导致发现急需的一流的选择性抑制剂f Meprin？然后呢？我们还将与肽合成、HTS和药物化学领域的专家合作。 我们的预期结果是一个明确的理解的作用，Meprin？然后呢？在系统性硬化症，这将导致一个更全面的了解机制，调节其进展，并可能导致新的治疗方法的发展。

DESCRIPTION: Meprin ? and ? are members of a superfamily of metzincin proteases implicated in systemic sclerosis. Studies indicate that the overexpression of Meprin ? and ? is correlated with increase deposition of fibrillar collagens in skin and other organs and tissues. This can potentially lead to kidney, lung, and heart fibrosis and eventual failure and death. The main obstacle in studying Meprin ? and ? role in systemic sclerosis is the lack of selective inhibitors. Most of the Meprin ? and ??inhibitors developed to date feature Zn-binding moieties that target the active site Zn. There are approximately 70 known human metalloproteases that have Zn in their active site, which leads to an off-target toxicity of Zn-binding inhibitors. Base on our preliminary results, we hypothesize that Meprin ? and ? selective inhibitors will be effective research tools in systemic sclerosis where Meprin ? and ? are implicated. There are currently no publicly available selective inhibitors of Meprin ? and ? metalloproteases. The overall aim of this project is to develop selective inhibitors of Meprin ? and ?. The specific aims of this proposal will focus on (1) HTS of the Scripps library which consists of > 640,000 compounds; (2) Medicinal chemistry and in vitro characterization of selective probes of Meprin ? and ?. Our laboratory is uniquely positioned to achieve these goals due to expertise in biology, biochemistry and drug/probe discovery for metalloproteases. We discovered a novel class of metalloprotease ADAM17 inhibitors that spare its closest analogue, ADAM10, and most common anti-targets (MMP-14 and -8). To our knowledge, we are the first laboratory to report ADAM17 inhibitors with such unique selectivity. Additionally, we discovered novel selective non-zinc-binding inhibitors of another metalloprotease, MMP-13 implicated in osteoarthritis. Most germane to the present proposal, both discoveries were made utilizing HTS either of NIH or TPIMS libraries in close collaboration with Scripps Research Institute Molecular Screening Center (co-headed by Dr. Scampavia and Mr. Spicer) and Dr. Fields. We strongly believe that HTS of Scripps library will result in discovery of much needed first-in-class selective inhibitors f Meprin ? and ?. We will also collaborate with experts in the fields of peptide synthesis, HTS, and medicinal chemistry. Our expected outcome is a clear understanding of the role of Meprin ? and ? in systemic sclerosis, which will lead to a more comprehensive knowledge about the mechanisms that regulate its progression and potentially result in the development of novel therapies.