HTS for selective inhibitors of Meprin alpha and beta

Meprin α 和 β 选择性抑制剂的 HTS

• 批准号: 9546468
• 负责人: Dmitriy Minond
• 金额: $ 32.25万
• 依托单位: NOVA SOUTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-24 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9546468
• 关键词: Active Sites; Binding; Biochemical; Biochemistry; Biological Assay; Biology; Cessation of life; Collaborations; Collagen; Data; Degenerative polyarthritis; Deposition; Development; Disease; Enzymes; Failure; Fibrillar Collagen; Fibrosis; Goals; Grant; Heart; Human; In Vitro; Individual; Kidney; Knowledge; Laboratories; Lead; Libraries; Lung; Meprin; Metalloproteases; Molecular; Organ; Outcome; Peptide Hydrolases; Peptide Synthesis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Positioning Attribute; Readiness; Reporting; Research; Research Institute; Role; Skin; Spices; Systemic Scleroderma; Testing; Tissues; Toxic effect; United States National Institutes of Health; Zinc; analog; base; cheminformatics; collagenase 3; enzyme substrate; high throughput screening; in vivo; inhibitor/antagonist; member; meprin alpha; miniaturize; novel; novel therapeutic intervention; novel therapeutics; overexpression; public health relevance; screening; skin fibrosis; small molecule inhibitor; therapeutic target; tool

DESCRIPTION: Meprin α and ß are members of a superfamily of metzincin proteases implicated in systemic sclerosis. Studies indicate that the overexpression of Meprin α and ß 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 α and ß role in systemic sclerosis is the lack of selective inhibitors. Most of the Meprin α and ß 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 α and ß selective inhibitors will be effective research tools in systemic sclerosis where Meprin α and ß are implicated. There are currently no publicly available selective inhibitors of Meprin α and ß metalloproteases. The overall aim of this project is to develop selective inhibitors of Meprin α and ß. 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 α and ß. 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 of Meprin α and ß. 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 α and ß 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.

产品说明： 甲氧苄氨嘧啶α和甲氧苄氨嘧啶是与系统性硬化症有关的甲氧苄氨嘧啶蛋白酶超家族的成员。研究表明，Meprin α和Meprin β的过表达与皮肤和其他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 α和Meprin role在系统性硬化症中的主要障碍是缺乏选择性抑制剂。迄今为止开发的大多数Meprin α和Meprin α抑制剂都具有靶向活性位点Zn的Zn结合部分。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。 基于我们的初步结果，我们假设Meprin α和Meprin α选择性抑制剂将是Meprin α和Meprin α相关的系统性硬化症的有效研究工具。目前还没有公开的Meprin α和Meprin β金属蛋白酶的选择性抑制剂。 本项目的总体目标是开发Meprin α和Meprin β的选择性抑制剂。具体目标 本研究的重点是：（1）Scripps库的HTS，该库包含超过640，000种化合物;（2）Meprin α和Meprin α选择性探针的药物化学和体外表征。 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Meprin α和Meprin α的第一个选择性抑制剂。我们还将与肽合成，HTS和药物化学领域的专家合作。 我们的预期结果是清楚地了解Meprin α和Meprin在系统性硬化症中的作用，这将导致更全面地了解调节其进展的机制，并可能导致新疗法的开发。

项目成果

Discovery and Optimization of Selective Inhibitors of Meprin α (Part I).

• DOI: 10.3390/ph14030203
• 发表时间: 2021-02-28
• 期刊: Pharmaceuticals (Basel, Switzerland)
• 作者: Hou S;Diez J;Wang C;Becker-Pauly C;Fields GB;Bannister T;Spicer TP;Scampavia LD;Minond D
• 通讯作者: Minond D

Discovery and Optimization of Selective Inhibitors of Meprin α (Part II).

• DOI: 10.3390/ph14030197
• 发表时间: 2021-02-27
• 期刊: Pharmaceuticals (Basel, Switzerland)
• 作者: Wang C;Diez J;Park H;Spicer TP;Scampavia LD;Becker-Pauly C;Fields GB;Minond D;Bannister TD
• 通讯作者: Bannister TD