Upgrading a Natural Product: Inhibition of Human β‐Tryptase by Cyclotheonamide Analogues
Upgrading a Natural Product: Inhibition of Human β‐Tryptase by Cyclotheonamide Analogues
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天然产物的升级：环草酰胺类似物对人类 β 类胰蛋白酶的抑制
DOI：
10.1002/cmdc.200900484
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发表时间：
2010
期刊：
影响因子：
3.4
通讯作者：
Sommerhoff CP
中科院分区：
文献类型：
--
作者：
Schaschke N;Sommerhoff CP
哮喘是一个严重的全球健康问题。据目前估计，全世界各种年龄和种族背景的多达3亿人患有这种下呼吸道慢性阻塞性疾病虽然以皮质类固醇和b2肾上腺素受体激动剂为基础的现有治疗方法已经达到了很高的水平，但仍迫切需要新的治疗策略[2,3]。在此背景下，人类b-胰蛋白酶，一种具有胰蛋白酶样活性的丝氨酸蛋白酶（clan PA, family S1）[4,5]作为一种有前景的新药物靶点已成为人们关注的焦点该酶几乎只在肥大细胞中以前-前蛋白的形式表达，然后由组织蛋白酶c以肝素依赖的方式加工成成熟的形式[7,8]。它以酶活性形式储存在分泌颗粒中，占肥大细胞全部蛋白质含量的20%作为对过敏刺激的反应，这些细胞被ige介导的过程激活后，通过胞外作用将b-胰蛋白酶与其他炎症介质（如组胺和肝素蛋白多糖）一起释放到周围组织中越来越多的研究指出，这种分泌的蛋白酶在调节支气管张力、气道炎症和组织重塑（哮喘的标志）中起着关键作用。特别是，b-胰蛋白酶能降解和失活神经肽血管活性肠肽（VIP）[10]和降钙素基因相关肽（CGRP）[11]，因此被认为会影响气道平滑肌的张力，导致支气管收缩。此外，b-tryptase被证明可以诱导水肿的形成[12,13]，能够招募中性粒细胞和嗜酸性粒细胞[14-16]，并作为气道平滑肌细胞增殖的丝裂原。[17,18]事实上，雾化的人b-胰蛋白酶会导致过敏羊的支气管收缩、气道炎症和高反应性。[19-21]因此，人们投入了大量的努力来开发选择性阻断b-胰蛋白酶b[6]肽解活性的抑制剂，并在临床IIa期研究中获得了抑制剂APC-366的原理证明。cyclotheonamide是一类结构相关的海洋环状五肽，具有抑制胰蛋白酶样丝氨酸蛋白酶的作用，其中以cyclotheonamide A最为突出。环甲酰胺A与胰蛋白酶和凝血酶配合物的x射线晶体结构阐明了它们的结合模式。[23,24]由于大内酰胺化稳定了延伸的肽构象，该抑制剂不仅可以以类似底物的方式处理S1袋，还可以处理S1、S2和S3袋（图1）。S1的
Asthma is a serious global health problem. It is currently estimated that as many as 300 million people worldwide, of all ages and ethnic backgrounds, suffer from this chronic obstructive disease of the lower airways.[1] Although the established treatments based on corticosteroids and b2-adrenoceptor agonists have reached a high standard,[2, 3] there is still a pressing demand for new therapeutic strategies. In this context, human b-tryptase, a serine protease with trypsin-like activity (clan PA, family S1),[4, 5] has been the focus of interest as a promising new drug target.[6] This enzyme is almost exclusively expressed in mast cells as a pre-pro-protein, which is then processed into its mature form in a heparin-dependent manner by cathepsin C.[7, 8] It is stored in the enzymatically active form within secretory granules and accounts for up to 20% of the entire protein content of mast cells.[5] Upon activation by an IgE-mediated process as a response to allergic stimuli, these cells release b-tryptase along with other inflammatory mediators such as histamine and heparin proteoglycans into the surrounding tissue by exocytosis.[9] An increasing number of studies point to a pivotal role of this secreted protease in modulating bronchial tone, airway inflammation, and tissue remodeling, the hallmarks of asthma. In particular, b-tryptase degrades and inactivates the neuropeptides vasoactive intestinal peptide (VIP)[10] and calcitonin-gene-related peptide (CGRP),[11] and thus has been proposed to affect the tone of airway smooth muscle leading to bronchial constriction. Furthermore, b-tryptase was shown to induce the formation of edema,[12, 13] is able to recruit neutrophils and eosinophils,[14–16] and acts as a mitogen for the proliferation of airway smooth muscle cells.[17, 18] Indeed, aerosolized human b-tryptase causes bronchial constriction, airway inflammation, and hyperresponsiveness in allergic sheep.[19–21] Intensive efforts were therefore undertaken to develop inhibitors that selectively block the peptidolytic activity of b-tryptase,[6] and proof-ofprinciple has been obtained with the inhibitor APC-366 in a clinical phase IIa study.[22]Cyclotheonamides, most prominent among them cyclotheonamide A, constitute a family of structurally related cyclic pentapeptides of marine origin that inhibit trypsin-like serine proteases. Their binding mode has been elucidated by the X-ray crystal structures of cyclotheonamide A in complex with trypsin and thrombin.[23, 24] Due to an extended peptide conformation that is stabilized by macrolactamization, the inhibitor allows to address, in a substrate-like manner, not only the S1 pocket, but also the S1о, S2, and S3 pockets (Figure 1). The S1
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人肥大细胞类胰蛋白酶减弱降钙素基因相关肽的血管舒张活性。
影响因子：
5.8
作者：
A. F. Walls;S. D. Brain;Anita Desai;P. J. Jose;Elaine Hawkings;M. K. Church;Timothy Williams
通讯作者：
Timothy Williams
环草酰胺衍生物：合成和凝血酶抑制。
影响因子：
3.5
作者：
B. Maryanoff;H. Zhang;M. Greco;K. Glover;J. Kauffman;P. Andrade‐Gordon
通讯作者：
P. Andrade‐Gordon
双环均肽库：固相合成的合成策略比较。
影响因子：
--
作者：
M. Teixidó;M. Altamura;L. Quartara;A. Giolitti;C. Maggi;E. Giralt;F. Albericio
通讯作者：
F. Albericio
影响因子：
3.3
作者：
Berger, P;Perng, DW;Walls, AF
通讯作者：
Walls, AF
使用 Ac-(D)Phe-Pro-boroArg-OH 及其赖氨酸、脒、高赖氨酸和鸟氨酸类似物进行凝血酶的动力学和晶体学研究。
影响因子：
2.9
作者：
P. Weber;S. L. Lee;F. Lewandowski;M. Schadt;C. W. Chang;C. Kettner
通讯作者：
C. Kettner