A high-affinity competitive inhibitor of type A botulinum neurotoxin protease activity
A high-affinity competitive inhibitor of type A botulinum neurotoxin protease activity
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DOI：
10.1016/s0014-5793(02)03738-9
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发表时间：
2002-12-18
期刊：
影响因子：
3.5
通讯作者：
Stafford, RG
中科院分区：
文献类型：
--
作者：
Schmidt, JJ;Stafford, RG
肽N-乙酰基-CRATKML-酰胺是A型肉毒杆菌神经毒素（BoNT A）蛋白酶活性的有效抑制剂[施密特等人，FEBS Lett. 435（1998）61-64]。为了改善抑制剂结合，通过用其他含巯基化合物取代半胱氨酸来修饰肽。合成了10种肽。一种肽使卡托普利的结构适应BoNT A的结合要求，但它是弱抑制剂，表明血管紧张素转换酶不是BoNT A抑制剂开发的良好模型。然而，用2-巯基-3-苯基丙酰基代替半胱氨酸产生了Ki为330 nM的肽，这是迄今报道的BoNT A蛋白酶活性的最佳抑制剂。抑制剂的另外的修饰揭示了对于结合重要的结构元件，并且支持我们的早期发现，即除了P-1'精氨酸之外，BoNT A上的亚位点对于特定的氨基酸侧链不是高度特异性的。(C)2002年由Elsevier Science B. V.代表欧洲生物化学学会联合会出版。
The peptide N-acetyl-CRATKML-amide is an effective inhibitor of type A botulinum neurotoxin (BoNT A) protease activity [Schmidt et al., FEBS Lett. 435 (1998) 61-64]. To improve inhibitor binding, the peptide was modified by replacing cysteine with other sulfhydryl-containing compounds. Ten peptides were synthesized. One peptide adapted the structure of captopril to the binding requirements of BoNT A, but it was a weak inhibitor, suggesting that angiotensin-converting enzyme is not a good model for BoNT A inhibitor development. However, replacing cysteine with 2-mercapto-3-phenylpropionyl yielded a peptide with K-i of 330 nM, the best inhibitor of BoNT A protease activity reported to date. Additional modifications of the inhibitor revealed structural elements important for binding and supported our earlier findings that, with the exception of P-1' arginine, subsites on BoNT A are not highly specific for particular amino acid side chains. (C) 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.