Peptide exosite inhibitors of factor VIIa as anticoagulants
Peptide exosite inhibitors of factor VIIa as anticoagulants
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DOI：
10.1038/35006574
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发表时间：
2000-03-30
期刊：
影响因子：
64.8
通讯作者：
Lazarus, RA
中科院分区：
文献类型：
--
作者：
Dennis, MS;Eigenbrot, C;Lazarus, RA
利用噬菌体M13上展示的天然肽库靶向组织因子-因子VIIa复合物，已经衍生出有效的抗凝剂。这些肽特异性地阻断因子X的活化，其中位抑制浓度为1 nM，并选择性地抑制组织因子依赖性凝血。相反，它们通过与因子VIIa蛋白酶结构域上的外部位点结合而起作用，并且非竞争性地抑制因子X的活化和酰胺分解活性。一种这样的肽（E-76）在溶液中具有通过NMR光谱确定的明确的结构，其类似于与因子VIIa复合时的X射线晶体结构。这些结构和功能研究表明涉及因子VIIa的活化环的抑制的变构“开关”机制，并且代表用于开发丝氨酸蛋白酶抑制剂的新框架。
Potent anticoagulants have been derived by targeting the tissue factor-factor VIIa complex with naive peptide libraries displayed on M13 phage, The peptides specifically block the activation of factor X with a median inhibitory concentration of 1 nM and selectively inhibit tissue-factor-dependent clotting, The peptides do not bind to the active site of factor VIIa; rather, they work by binding to an exosite on the factor VIIa protease domain, and non-competitively inhibit activation of factor X and amidolytic activity. One such peptide (E-76) has a well defined structure in solution determined by NMR spectroscopy that is similar to the X-ray crystal structure when complexed with factor VIIa, These structural and functional studies indicate an allosteric 'switch' mechanism of inhibition involving an activation loop of factor VIIa and represent a new framework for developing inhibitors of serine proteases.