Development of Potential Peptidylarginine Deiminase Inhibitors

潜在肽基精氨酸脱亚胺酶抑制剂的开发

• 批准号: 7053257
• 负责人: Ryan Edward Looper
• 金额: $ 4.6万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7053257
• 关键词: active sites; amidinohydrolase; binding sites; combinatorial chemistry; copper; cyclization; enzyme inhibitors; isozymes; molecular probes; peptide library; postdoctoral investigator; posttranslational modifications; protein folding; rhodium; small molecule

DESCRIPTION (provided by applicant): This proposal aims to synthesize a library of compounds that are pre-disposed to inhibit peptidylarginine deiminases (PADs), enzymes that have recently been implicated in chromatin modification. In concert with the known small molecule inhibitors of histone deacetylaces (tubacin) and peptidylarginine methyl transferases, these compounds may enable the dissection of these epigenetic marks and their implications in gene regulation and oncogenesis. Enzymes that modify arginine generally accept the free amino acid as controlled by a guarded active site. Recent crystallographic evidence shows that PADs have a region around the active site that recognizes peptide substrates. It may be generalized that this binding surface is isoform specific, between PADs1-4, allowing the selective recognition of target proteins by small molecules. Having no known specific inhibitors, we wish to exploit diversity oriented synthesis to generate a library of compounds that explore binding interactions with this peptide recognition surface. Elaborating a novel Rh(ll) catalyzed folding pathway, six distinct molecular skeletons will be prepared. We aim to exploit a Cu(l) catalyzed cycloaddition reaction to terminate these skeletons with arginine pharmacophores. For screening purposes, this collection of potential inhibitors will be synthesized on a platform capable of delivering up to 20 mg of compound, greatly expediting the process of validating their biological activity.

描述（由申请人提供）：该提案旨在合成预先介绍的化合物库，以抑制肽基金蛋白脱氨酸酶（PADS），这些酶最近与染色质修饰有关。这些化合物与已知的组蛋白脱乙酰基（tubacin）和肽甲基甲基转移酶的小分子抑制剂一致，这些化合物可以使这些表观遗传标记及其在基因调节和肿瘤发生中的影响。修改精氨酸的酶通常接受由受保护的活性位点控制的游离氨基酸。最近的晶体学证据表明，垫子周围有一个识别肽底物的区域。可以概括地认为，这种结合表面在PADS1-4之间是同工型特异性的，从而可以通过小分子对靶蛋白进行选择性识别。没有已知的特异性抑制剂，我们希望利用面向多样性的合成来生成探索与该肽识别表面结合相互作用的化合物库。详细阐述了一种新型的RH（LL）催化折叠途径，将制备六个不同的分子骨骼。我们旨在利用Cu（L）催化的环加成反应，以用精氨酸药理终止这些骨架。出于筛查目的，该潜在抑制剂的集合将在能够输送20毫克化合物的平台上合成，从而大大加快了验证其生物学活性的过程。