5-Oxo-7a-methyl-2,3,5,6,7,7a-hexahydro-pyrrolo<2,1-β>thiazol-carbonsaeure-(3) | 17279-63-9

• 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: 5-Oxo-7a-methyl-2,3,5,6,7,7a-hexahydro-pyrrolo<2,1-β>thiazol-carbonsaeure-(3)
• 英文别名: 7a-methyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carboxylic acid；7a-Methyl-5-oxohexahydropyrrolo[2,1-b][1,3]thiazole-3-carboxylic acid；7a-methyl-5-oxo-2,3,6,7-tetrahydropyrrolo[2,1-b][1,3]thiazole-3-carboxylic acid
• CAS: 17279-63-9
• 化学式: C₈H₁₁NO₃S
• mdl: MFCD00553439
• 分子量: 201.246
• InChiKey: LVAMAFDAANOMGN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  82.9
• 氢给体数：
  1
• 氢受体数：
  4

安全信息

• 海关编码：
  2934100090

反应信息

• 作为反应物：
  描述：

  5-Oxo-7a-methyl-2,3,5,6,7,7a-hexahydro-pyrrolo<2,1-β>thiazol-carbonsaeure-(3) 在 碘 、 2-肟氰乙酸乙酯 、 N,N'-二异丙基碳二亚胺 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 N,N'-(disulfanediylbis(ethane-2,1-diyl))bis(7a-methyl-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carboxamide)
  参考文献：
  名称：

  Modulation of Amyloidogenic Protein Self-Assembly Using Tethered Small Molecules

  摘要：

  Protein-protein interactions (PPIs) are involved in many of life's essential biological functions yet are also an underlying cause of several human diseases, including amyloidosis. The modulation of PPIs presents opportunities to gain mechanistic insights into amyloid assembly, particularly through the use of methods which can trap specific intermediates for detailed study. Such information can also provide a starting point for drug discovery. Here, we demonstrate that covalently tethered small molecule fragments can be used to stabilize specific oligomers during amyloid fibril formation, facilitating the structural characterization of these assembly intermediates. We exemplify the power of covalent tethering using the naturally occurring truncated variant (ΔN6) of the human protein β2-microglobulin (β2m), which assembles into amyloid fibrils associated with dialysis-related amyloidosis. Using this approach, we have trapped tetramers formed by ΔN6 under conditions which would normally lead to fibril formation and found that the degree of tetramer stabilization depends on the site of the covalent tether and the nature of the protein-fragment interaction. The covalent protein-ligand linkage enabled structural characterization of these trapped, off-pathway oligomers using X-ray crystallography and NMR, providing insight into why tetramer stabilization inhibits amyloid assembly. Our findings highlight the power of "post-translational chemical modification" as a tool to study biological molecular mechanisms.

  DOI：

  10.1021/jacs.0c10629

文献信息

• Modulation of Amyloidogenic Protein Self-Assembly Using Tethered Small Molecules
  作者：Emma E. Cawood、Nicolas Guthertz、Jessica S. Ebo、Theodoros K. Karamanos、Sheena E. Radford、Andrew J. Wilson

  DOI：10.1021/jacs.0c10629

  日期：2020.12.9

  Protein-protein interactions (PPIs) are involved in many of life's essential biological functions yet are also an underlying cause of several human diseases, including amyloidosis. The modulation of PPIs presents opportunities to gain mechanistic insights into amyloid assembly, particularly through the use of methods which can trap specific intermediates for detailed study. Such information can also provide a starting point for drug discovery. Here, we demonstrate that covalently tethered small molecule fragments can be used to stabilize specific oligomers during amyloid fibril formation, facilitating the structural characterization of these assembly intermediates. We exemplify the power of covalent tethering using the naturally occurring truncated variant (ΔN6) of the human protein β2-microglobulin (β2m), which assembles into amyloid fibrils associated with dialysis-related amyloidosis. Using this approach, we have trapped tetramers formed by ΔN6 under conditions which would normally lead to fibril formation and found that the degree of tetramer stabilization depends on the site of the covalent tether and the nature of the protein-fragment interaction. The covalent protein-ligand linkage enabled structural characterization of these trapped, off-pathway oligomers using X-ray crystallography and NMR, providing insight into why tetramer stabilization inhibits amyloid assembly. Our findings highlight the power of "post-translational chemical modification" as a tool to study biological molecular mechanisms.