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Nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) and its inhibitors
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2017-02-09 00:00:00 , DOI: 10.1039/c7md00015d Sang-Yong Lee 1, 2, 3, 4, 5 , Christa E. Müller 1, 2, 3, 4, 5
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2017-02-09 00:00:00 , DOI: 10.1039/c7md00015d Sang-Yong Lee 1, 2, 3, 4, 5 , Christa E. Müller 1, 2, 3, 4, 5
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Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1, EC 3.1.4.1) is a metalloenzyme that belongs to the NPP family, which comprises seven subtypes (NPP1-7). NPP1 hydrolyzes a wide range of phosphodiester bonds, e.g. in nucleoside triphosphates, (cyclic) dinucleotides, and nucleotide sugars yielding nucleoside 5′-monophosphates as products. Its main substrate is ATP which is cleaved to AMP and diphosphate. The enzyme is involved in various biological processes including bone mineralization, soft-tissue calcification, insulin receptor signalling, cancer cell proliferation and immune modulation. Therefore, NPP1 inhibitors have potential as novel drugs, e.g. for (immuno)oncology. In the last two decades several inhibitors of NPP1 derived from nucleotide- or non-nucleotide scaffolds have been developed. The most potent and selective NPP1-inhibitory substrate analog is adenosine 5′-α,β-methylene-γ-thiotriphosphate (Ki = 20 nM vs. p-Nph-5′-TMP, human membrane-bound NPP1). Non-nucleotide-derived NPP1 inhibitors comprise polysulfonates, polysaccharides, polyoxometalates and small heterocyclic compounds. The polyoxometalate [TiW11CoO40]8− (PSB-POM141) is the most potent and selective NPP1 inhibitor described to date (Ki = 1.46 nM vs. ATP, human soluble NPP1); it displays an allosteric mechanism of inhibition and represents a useful pharmacological tool for evaluating the potential of NPP1 as a novel drug target.
中文翻译：
核苷酸焦磷酸酶/磷酸二酯酶1（NPP1）及其抑制剂
Ecto-核苷酸焦磷酸酶/磷酸二酯酶1（NPP1，EC 3.1.4.1）是一种金属酶，属于NPP家族，包括七个亚型（NPP1-7）。NPP1水解广泛的磷酸二酯键，例如在核苷三磷酸，（环状）二核苷酸和核苷酸糖中水解，生成核苷5'-单磷酸酯作为产物。它的主要底物是ATP，可裂解为AMP和二磷酸。该酶参与各种生物过程，包括骨骼矿化，软组织钙化，胰岛素受体信号传导，癌细胞增殖和免疫调节。因此，NPP1抑制剂具有作为新药的潜力，例如用于（免疫）肿瘤学。在最近的二十年中，已经开发了几种衍生自核苷酸或非核苷酸支架的NPP1抑制剂。最有效和最具选择性的NPP1抑制底物类似物是5'-α，β-亚甲基-γ-硫代三磷酸腺苷（K i = 20 nM ，对-Nph-5'-TMP，人膜结合NPP1）。非核苷酸来源的NPP1抑制剂包括多磺酸盐，多糖，多金属氧酸盐和小的杂环化合物。多金属氧酸盐[TiW 11 CoO 40 ] 8-（PSB-POM141）是迄今为止描述的最有效和最具选择性的NPP1抑制剂（K i = 1.46 nMvs 。ATP，人类可溶性NPP1）；它显示出抑制作用的变构机制，并代表了一种有用的药理学工具，可用于评估NPP1作为新型药物靶标的潜力。
更新日期：2017-05-31
中文翻译：
核苷酸焦磷酸酶/磷酸二酯酶1（NPP1）及其抑制剂
Ecto-核苷酸焦磷酸酶/磷酸二酯酶1（NPP1，EC 3.1.4.1）是一种金属酶，属于NPP家族，包括七个亚型（NPP1-7）。NPP1水解广泛的磷酸二酯键，例如在核苷三磷酸，（环状）二核苷酸和核苷酸糖中水解，生成核苷5'-单磷酸酯作为产物。它的主要底物是ATP，可裂解为AMP和二磷酸。该酶参与各种生物过程，包括骨骼矿化，软组织钙化，胰岛素受体信号传导，癌细胞增殖和免疫调节。因此，NPP1抑制剂具有作为新药的潜力，例如用于（免疫）肿瘤学。在最近的二十年中，已经开发了几种衍生自核苷酸或非核苷酸支架的NPP1抑制剂。最有效和最具选择性的NPP1抑制底物类似物是5'-α，β-亚甲基-γ-硫代三磷酸腺苷（K i = 20 nM ，对-Nph-5'-TMP，人膜结合NPP1）。非核苷酸来源的NPP1抑制剂包括多磺酸盐，多糖，多金属氧酸盐和小的杂环化合物。多金属氧酸盐[TiW 11 CoO 40 ] 8-（PSB-POM141）是迄今为止描述的最有效和最具选择性的NPP1抑制剂（K i = 1.46 nMvs 。ATP，人类可溶性NPP1）；它显示出抑制作用的变构机制，并代表了一种有用的药理学工具，可用于评估NPP1作为新型药物靶标的潜力。
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