HTS for selective inhibitors of Meprin alpha and beta

描述：美普林？然后呢?是与系统性硬化症有关的甲锌蛋白酶超家族的成员。研究表明，Meprin ？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，最终导致衰竭和死亡。研究美普林的主要障碍是什么？然后呢?在系统性硬化症中的作用是缺乏选择性抑制剂。大部分的美普林？和? ?迄今为止开发的抑制剂具有针对活性位点Zn的锌结合部分。大约有70种已知的人类金属蛋白酶在其活性位点含有锌，这导致锌结合抑制剂的脱靶毒性。根据我们的初步结果，我们假设美普林？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。然后呢?有牵连的。目前还没有公开的选择性美普兰抑制剂。然后呢?metalloproteases。该项目的总体目标是开发Meprin ？和?。具体目标

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.