Selective Inhibition of Collagen Prolyl 4-Hydroxylase in Human Cells.
Selective Inhibition of Collagen Prolyl 4-Hydroxylase in Human Cells.
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DOI：
10.1021/acschembio.5b00749
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发表时间：
2016-01-15
影响因子：
4
通讯作者：
Raines RT
中科院分区：
文献类型：
--
作者：
Vasta JD;Andersen KA;Deck KM;Nizzi CP;Eisenstein RS;Raines RT
胶原蛋白是动物体内含量最丰富的蛋白质。它的过度生产与纤维化和癌症转移有关。胶原蛋白的稳定性依赖于翻译后修饰，最常见的是胶原蛋白脯氨基4-羟基酶(CP4Hs)对胶原链的羟化作用。在CP4Hs的催化作用下，有一个铁辅因子将脯氨酸残基转化为4个羟基脯氨酸残基，这对成熟胶原的构象稳定性是必不可少的。3，4-二羟基苯甲酸乙酯(EDHB)是细胞内常用的P4H抑制剂，但存在效价低、选择性差、脱靶等缺点，导致铁缺乏。2，2‘-联吡啶的二羧酸盐是已知的最有效的CP4H抑制剂之一，但对游离铁有很高的亲和力。对双杂芳基化合物的筛选表明，用噻唑部分取代一个吡啶基团保持了效力并提高了选择性。2-(5-羧基噻唑-2-基)吡啶-5-羧酸二酯对人体细胞具有生物利用度，在不引起全身毒性或破坏铁稳态的浓度下抑制胶原的生物合成。这些数据为CP4H提供了一种有效和选择性的探针，并为开发一类新型的抗纤维化和抗肿瘤药物提供了潜在的线索。
Collagen is the most abundant protein in animals. Its overproduction is associated with fibrosis and cancer metastasis. The stability of collagen relies on post-translational modifications, the most prevalent being the hydroxylation of collagen strands by collagen prolyl 4-hydroxylases (CP4Hs). Catalysis by CP4Hs enlists an iron cofactor to convert proline residues to 4 hydroxyproline residues, which are essential for the conformational stability of mature collagen. Ethyl 3,4-dihydroxybenzoate (EDHB) is commonly used as a “P4H” inhibitor in cells, but suffers from low potency, poor selectivity, and off-target effects that cause iron deficiency. Dicarboxylates of 2,2′-bipyridine are among the most potent known CP4H inhibitors but suffer from a high affinity for free iron. A screen of biheteroaryl compounds revealed that replacing one pyridyl group with a thiazole moiety retains potency and enhances selectivity. A diester of 2 (5-carboxythiazol-2-yl)pyridine-5-carboxylic acid is bioavailable to human cells and inhibits collagen biosynthesis at concentrations that neither cause general toxicity nor disrupt iron homeostasis. These data anoint a potent and selective probe for CP4H and a potential lead for the development of a new class of antifibrotic and antimetastatic agents.