HTS for selective inhibitors of Meprin alpha and beta

描述：梅普林？然后呢？是与系统性硬化症有关的梅津星蛋白水解酶超家族的成员。研究表明，Meprin？的过度表达？然后呢？与皮肤和其他器官和组织中纤维状胶原沉积增加有关。这可能会导致肾、肺和心脏纤维化，并最终导致衰竭和死亡。研究梅普林的主要障碍是什么？然后呢？系统性硬化症的作用是缺乏选择性抑制剂。大部分的梅普林？到目前为止开发的抑制剂的特点是以活性部位锌为靶点的锌结合部分。大约有70种已知的人类金属蛋白水解酶的活性部位含有锌，这导致了锌结合抑制剂的非靶点毒性。根据我们的初步结果，我们假设梅普林？然后呢？选择性抑制剂将成为系统性硬化症的有效研究工具，美普林在哪里？然后呢？都有牵连。目前还没有公开可用的Meprin选择性抑制剂？然后呢？金属蛋白酶。该项目的总体目标是开发梅普林的选择性抑制剂？然后呢？具体目标 这项提案的重点将集中在(1)包含640,000种化合物的Scripps文库的HTS；(2)Meprin？选择性探针的药物化学和体外表征。然后呢？我们的实验室在生物、生物化学和金属蛋白酶药物/探针发现方面的专业知识使我们的实验室在实现这些目标方面具有得天独厚的优势。我们发现了一类新的金属蛋白酶ADAM17抑制剂，它省去了与其最接近的类似物ADAM10和最常见的抗靶标(MMP-14和-8)。据我们所知，我们是第一个报道具有如此独特选择性的ADAM17抑制剂的实验室。此外，我们发现了另一种金属蛋白酶的新型选择性非锌结合抑制剂，即与骨关节炎有关的基质金属蛋白酶-13。与本提案最为相关的是，这两项发现都是利用HTS的NIH或Tpims文库，与斯克里普斯研究所分子筛查中心(由斯坎维娅博士和斯派塞先生共同领导)和菲尔兹博士密切合作做出的。我们坚信，斯克里普斯文库的HTS将导致发现急需的Meprin？一类选择性抑制剂。然后呢？我们还将与肽合成、高温超导和药物化学领域的专家合作。我们预期的结果是对Meprin的作用有一个明确的理解？然后呢？这将导致对调节其进展的机制有更全面的了解，并可能导致新疗法的开发。

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.