Development of Potential Peptidylarginine Deiminase Inhibitors

描述（由申请人提供）：该提案旨在合成一个预先抑制肽精氨酸脱亚胺酶（PADs）的化合物库，这些酶最近被认为与染色质修饰有关。与已知的组蛋白去乙酰化酶（tubacin）和肽精氨酸甲基转移酶的小分子抑制剂一起，这些化合物可能使这些表观遗传标记的解剖及其在基因调控和肿瘤发生中的意义成为可能。修饰精氨酸的酶通常接受受保护活性位点控制的游离氨基酸。最近的晶体学证据表明，pad在活性位点周围有一个识别肽底物的区域。可以概括地说，该结合表面在PADs1-4之间具有异构体特异性，允许小分子选择性识别靶蛋白。由于没有已知的特异性抑制剂，我们希望利用多样性导向合成来生成一个化合物库，探索与该肽识别表面的结合相互作用。阐述了一种新的Rh（ll）催化折叠途径，制备了六个不同的分子骨架。我们的目标是利用Cu(l)催化的环加成反应，用精氨酸药物载体终止这些骨架。为了筛选目的，这一系列潜在的抑制剂将在一个能够递送高达20mg化合物的平台上合成，大大加快了验证其生物活性的过程。

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.