POTENT NEW INHIBITORS OF HUMAN RENIN
POTENT NEW INHIBITORS OF HUMAN RENIN
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DOI：
10.1038/299555a0
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发表时间：
1982-01-01
期刊：
影响因子：
64.8
通讯作者：
LEVER, AF
中科院分区：
文献类型：
--
作者：
SZELKE, M;LECKIE, B;LEVER, AF
肾酸性蛋白酶肾素选择性裂解其血浆底物血管紧张素原，释放十肽血管紧张素 I，十肽血管紧张素 I 又被羧二肽酶转化酶裂解，产生升压八肽血管紧张素 II1。人们普遍认为，肾素-血管紧张素系统在血压和电解质稳态中具有生理作用2，并且该系统的异常会导致某些形式的高血压3。我们之前表明，马血管紧张素原 (6-13) 八肽序列 2 中 Leu10-Leu11 易剪肽键的还原产生了犬血浆肾素的有效和选择性抑制剂 5。我们现在使用相同的方法来修改最近阐明的人血管紧张素原的N端序列6，并在此报告了在人血浆中内源性人肾素裂解肾素底物的高活性和物种特异性体外抑制剂的产生。人血管紧张素原的 (6-13) 八肽 H-112 只是人血浆肾素的弱抑制剂 (IC50= 313 µM)，而类似物 H-113（其中易断裂的 Leu-Val 键已被还原）的 IC50= 0.19 µM。 H-113 在 N 末端带有 Pro，在 C 末端带有 Lys7 延伸，得到十肽衍生物 H-142，进一步增加了抑制效力 (IC50= 10 nM)。我们认为，H-113 和 H-142 的高体外抑制效力是由于还原部分 -CH2-NH- 能够充当 (10-11) 肽键水解过程中形成的四面体过渡态的不可水解类似物。 H-113和H-142具有很强的种属特异性，并且对酸性蛋白酶中的肾素具有高度特异性：H-142在体外对人组织蛋白酶D或肾酸性蛋白酶在712μM的浓度下没有抑制作用。
The renal acid protease renin selectively cleaves its plasma substrate angiotensinogen to release the decapeptide angiotensin I, which in turn is cleaved by a carboxydipeptidase converting enzyme to yield the pressor octapeptide angiotensin II1. It is generally accepted that the renin–angiotensin system has a physiological role in blood pressure and electrolyte homeostasis2, and that abnormalities of the system contribute to certain forms of hypertension3. We previously showed that reduction of the Leu10–Leu11scissile peptide bond in the (6–13) octapeptide sequence2of equine angiotensinogen produced potent and selective inhibitors of canine plasma renin5. We have now used the same approach to modify the recently elucidated N-terminal sequence6of human angiotensinogen and report here the production of highly active and species-specificin vitroinhibitors of endogenous human renin cleaving renin substrate in human plasma. Whereas the (6–13) octapeptide H-112 of human angiotensinogen is only a weak inhibitor of human plasma renin (IC50= 313 µM), the analogue H-113, in which the scissile Leu–Val bond has been reduced, has IC50= 0.19 µM. Extension of H-113 with Pro at the N-terminus and with Lys at the C-terminus7, giving the decapeptide derivative H-142, increases inhibitory potency further (IC50= 10 nM). We believe that the highin vitroinhibitory potencies of H-113 and H-142 are due to the ability of the reduced moiety —CH2—NH— to act as a non-hydrolysable analogue of the tetrahedral transition state formed during hydrolysis of the (10–11) peptide bond. H-113 and H-142 are strongly species specific, and are highly specific for renin among acid proteases: H-142 has no inhibitory effectin vitroon human cathepsin D or renal acid protease at a concentration of 712 µM.