GWCIRSKPPICNPN

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: GWCIRSKPPICNPN
• 英文别名: cyclo[Arg-Ser-Lys-Pro-Pro-Ile-Cys(1)-Asn-Pro-Asn-Gly-Trp-Cys(1)-Ile]；2-[(1R,4S,7S,13S,19S,22S,25S,28S,31R,34S,40S,43S,49S)-19-(4-aminobutyl)-49-(2-amino-2-oxoethyl)-4,28-bis[(2S)-butan-2-yl]-25-[3-(diaminomethylideneamino)propyl]-22-(hydroxymethyl)-34-(1H-indol-3-ylmethyl)-3,6,12,18,21,24,27,30,33,36,39,42,48,51-tetradecaoxo-53,54-dithia-2,5,11,17,20,23,26,29,32,35,38,41,47,50-tetradecazapentacyclo[29.20.4.07,11.013,17.043,47]pentapentacontan-40-yl]acetamide
• 化学式: C₆₉H₁₀₅N₂₁O₁₇S₂
• 分子量: 1564.86
• InChiKey: AOMZQHHLSHFCGW-LQFZIJPOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.9
• 重原子数：
  109
• 可旋转键数：
  19
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  644
• 氢给体数：
  18
• 氢受体数：
  21

反应信息

• 作为产物：
  描述：

  Fmoc-甘氨酸 、 Fmoc-L-脯氨酸 、 Fmoc-L-异亮氨酸 、 Fmoc-L-色氨酸 、 Fmoc-L-天冬酰胺 、 FMOC-赖氨酸 、 Fmoc-L-丝氨酸 、 FMOC-L-精氨酸 、 芴甲氧羰基-L-半胱氨酸 在 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V) 、 N,N-二异丙基乙胺 、 哌啶 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.27h， 生成 GWCIRSKPPICNPN
  参考文献：
  名称：

  Improving the Selectivity of Engineered Protease Inhibitors: Optimizing the P2 Prime Residue Using a Versatile Cyclic Peptide Library

  摘要：

  Standard mechanism inhibitors are attractive design templates for engineering reversible serine protease inhibitors. When optimizing interactions between the inhibitor and target protease, many studies focus on the nonprimed segment of the inhibitor's binding loop (encompassing the contact beta-strand). However, there are currently few methods for screening residues on the primed segment. Here, we designed a synthetic inhibitor library (based on sunflower trypsin inhibitorI) for characterizing the P2' specificity of various serine proteases. Screening the library against 13 different proteases revealed unique P2' preferences for trypsin, ch-ymotrypsin, matriptase, plasmin, thrombin, four kallikrein-related peptidases, and several clotting factors. Using this information to modify existing engineered inhibitors yielded new variants that showed considerably improved selectivity, reaching up to 7000-fold selectivity over certain off-target proteases. Our study demonstrates the importance of the P2' residue in standard mechanism inhibition and unveils a new approach for screening P2' substitutions that will benefit future inhibitor engineering studies.

  DOI：

  10.1021/acs.jmedchem.5b01148

文献信息

• Improving the Selectivity of Engineered Protease Inhibitors: Optimizing the P2 Prime Residue Using a Versatile Cyclic Peptide Library
  作者：Simon J. de Veer、Conan K. Wang、Jonathan M. Harris、David J. Craik、Joakim E. Swedberg

  DOI：10.1021/acs.jmedchem.5b01148

  日期：2015.10.22

  Standard mechanism inhibitors are attractive design templates for engineering reversible serine protease inhibitors. When optimizing interactions between the inhibitor and target protease, many studies focus on the nonprimed segment of the inhibitor's binding loop (encompassing the contact beta-strand). However, there are currently few methods for screening residues on the primed segment. Here, we designed a synthetic inhibitor library (based on sunflower trypsin inhibitorI) for characterizing the P2' specificity of various serine proteases. Screening the library against 13 different proteases revealed unique P2' preferences for trypsin, ch-ymotrypsin, matriptase, plasmin, thrombin, four kallikrein-related peptidases, and several clotting factors. Using this information to modify existing engineered inhibitors yielded new variants that showed considerably improved selectivity, reaching up to 7000-fold selectivity over certain off-target proteases. Our study demonstrates the importance of the P2' residue in standard mechanism inhibition and unveils a new approach for screening P2' substitutions that will benefit future inhibitor engineering studies.