Ava1-YCVYR-βAla-SWSC-NH2, C4-C12 disulfide bridge

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: Ava1-YCVYR-βAla-SWSC-NH2, C4-C12 disulfide bridge
• 英文别名: deamino-Orn-Tyr-Cys(1)-Val-Tyr-Arg-bAla-Ser-Trp-Ser-Cys(1)-NH2；(4R,7S,10S,13S,20S,23S,26S,29R)-29-[[(2S)-2-(5-aminopentanoylamino)-3-(4-hydroxyphenyl)propanoyl]amino]-20-[3-(diaminomethylideneamino)propyl]-7,13-bis(hydroxymethyl)-23-[(4-hydroxyphenyl)methyl]-10-(1H-indol-3-ylmethyl)-6,9,12,15,19,22,25,28-octaoxo-26-propan-2-yl-1,2-dithia-5,8,11,14,18,21,24,27-octazacyclotriacontane-4-carboxamide
• 化学式: C₆₀H₈₄N₁₆O₁₅S₂
• 分子量: 1333.56
• InChiKey: MWVKQPRVSBVTAN-PUPYLTQUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.5
• 重原子数：
  93
• 可旋转键数：
  21
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  572
• 氢给体数：
  19
• 氢受体数：
  19

反应信息

• 作为产物：
  描述：

  Fmoc-L-缬氨酸 、 FMOC-beta-丙氨酸 、 5-[[芴甲氧羰基]氨基]戊酸 、 FMOC-O-叔丁基-L-丝氨酸 、 Fmoc-O-叔丁基-L-酪氨酸 、 Fmoc-S-三苯甲基-L-半胱氨酸 、 芴甲氧羰基-S-乙酰氨甲基-L-半胱氨酸 、 Fmoc-L-色氨酸(Boc)-OH 、 Fmoc-Pbf-L-精氨酸 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 、 4-甲基哌啶 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.45h， 生成 Ava1-YCVYR-βAla-SWSC-NH2, C4-C12 disulfide bridge
  参考文献：
  名称：

  Modifications of a Nanomolar Cyclic Peptide Antagonist for the EphA4 Receptor To Achieve High Plasma Stability

  摘要：

  EphA4 is a receptor tyrosine kinase with a critical role in repulsive axon guidance and synaptic function. However, aberrant EphA4 activity can inhibit neural repair after injury and exacerbate neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimers. We previously identified the cyclic peptide APY-d2 (APYCVYR beta ASWSC-NH2, containing a disulfide bond) as a potent and selective EphA4 antagonist. However, APY-d2 lacks sufficient plasma stability to be useful for EphA4 inhibition in vivo through peripheral administration. Using structureactivity relationship studies, we show that protecting the peptide N-terminus from proteolytic degradation dramatically increases the persistence of the active peptide in plasma and that a positively charged peptide N-terminus is essential for high EphA4 binding affinity. Among several improved APY-d2 derivatives, the cyclic peptides APY-d3 (beta APYCVYR beta AEWEC-NH2) and APY-d4 (beta APYCVYR beta AEWEC-NH2) combine high stability in plasma and cerebrospinal fluid with slightly enhanced potency. These properties make them valuable research tools and leads toward development of therapeutics for neurological diseases.

  DOI：

  10.1021/acsmedchemlett.6b00132