cyclo(1β-7β)(CRADTLC)-NH2

• 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: cyclo(1β-7β)(CRADTLC)-NH2
• 英文别名: H-Cys(1)-Arg-Ala-Asp-Thr-Leu-Cys(1)-NH2；2-[(4R,7S,10S,13S,16S,19S,22R)-22-amino-4-carbamoyl-19-[3-(diaminomethylideneamino)propyl]-10-[(1R)-1-hydroxyethyl]-16-methyl-7-(2-methylpropyl)-6,9,12,15,18,21-hexaoxo-1,2-dithia-5,8,11,14,17,20-hexazacyclotricos-13-yl]acetic acid
• 化学式: C₂₉H₅₁N₁₁O₁₀S₂
• 分子量: 777.924
• InChiKey: BDJFRNGYRVEUHX-AECBWZJCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -6.3
• 重原子数：
  52
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  416
• 氢给体数：
  12
• 氢受体数：
  14

反应信息

• 作为产物：
  描述：

  Fmoc-L-亮氨酸 、 Fmoc-L-天冬氨酸 、 Fmoc-Thr-OH 、 芴甲氧羰基-L-半胱氨酸 、 alkaline earth salt of/the/ methylsulfuric acid 、 alkaline earth salt of/the/ methylsulfuric acid 生成 cyclo(1β-7β)(CRADTLC)-NH2
  参考文献：
  名称：

  Selective α4β7 Integrin Antagonists and Their Potential as Antiinflammatory Agents

  摘要：

  The accumulation of leukocytes in various tissues contributes to the pathogenesis of numerous human autoimmune diseases. The integrin alpha4beta7, expressed on the surface of B and T lymphocytes, plays an essential role in lymphocyte trafficking throughout the gastrointestinal (GI) tract via interaction with its primary ligand, mucosal addressin cell adhesion molecule (MAdCAM). Elevated MAdCAM expression in the intestines and liver has been linked to GI-associated autoimmune disorders, including Crohn's disease, ulcerative colitis, and hepatitis C. Monoclonal antibodies that block the interaction of alpha4beta7 with MAdCAM inhibit lymphocyte homing to murine intestines without effecting migration to peripheral organs; this suggests that alpha4beta7-selective antagonists might be useful as GI specific antiinflammatory agents. Here, we report the discovery of highly potent and selective alpha4beta7 antagonists affinity selected from a random peptide-phage library. Subsequent optimization of initial peptide leads afforded alpha4beta7-selective heptapeptide inhibitors that competitively inhibit binding to MAdCAM in vitro and inhibit lymphocyte homing to murine intestines in vivo. Substitution of a single carboxylate moiety alters selectivity for alpha4beta7 by more than 500-fold to afford a potent and selective alpha4beta1 antagonist. The antagonists described here are the first peptides to demonstrate potency and selectivity for alpha4beta7 compared to,other integrins.

  DOI：

  10.1021/jm020033k

文献信息

• Selective α4β7 Integrin Antagonists and Their Potential as Antiinflammatory Agents
  作者：Nathan J. P. Dubree、Dean R. Artis、Georgette Castanedo、James Marsters、Daniel Sutherlin、Lisa Caris、Kevin Clark、Susan M. Keating、Maureen H. Beresini、Henry Chiu、Sherman Fong、Henry B. Lowman、Nicholas J. Skelton、David Y. Jackson

  DOI：10.1021/jm020033k

  日期：2002.8.1

  The accumulation of leukocytes in various tissues contributes to the pathogenesis of numerous human autoimmune diseases. The integrin alpha4beta7, expressed on the surface of B and T lymphocytes, plays an essential role in lymphocyte trafficking throughout the gastrointestinal (GI) tract via interaction with its primary ligand, mucosal addressin cell adhesion molecule (MAdCAM). Elevated MAdCAM expression in the intestines and liver has been linked to GI-associated autoimmune disorders, including Crohn's disease, ulcerative colitis, and hepatitis C. Monoclonal antibodies that block the interaction of alpha4beta7 with MAdCAM inhibit lymphocyte homing to murine intestines without effecting migration to peripheral organs; this suggests that alpha4beta7-selective antagonists might be useful as GI specific antiinflammatory agents. Here, we report the discovery of highly potent and selective alpha4beta7 antagonists affinity selected from a random peptide-phage library. Subsequent optimization of initial peptide leads afforded alpha4beta7-selective heptapeptide inhibitors that competitively inhibit binding to MAdCAM in vitro and inhibit lymphocyte homing to murine intestines in vivo. Substitution of a single carboxylate moiety alters selectivity for alpha4beta7 by more than 500-fold to afford a potent and selective alpha4beta1 antagonist. The antagonists described here are the first peptides to demonstrate potency and selectivity for alpha4beta7 compared to,other integrins.