Development of peptidyl prolyl isomerase Pin1 inhibitors based on thioamide isomerization energy

基于硫代酰胺异构化能的肽基脯氨酰异构酶Pin1抑制剂的开发

• 批准号: 25670059
• 负责人: NAKAGAWA Hidehiko
• 金额: $ 2.5万
• 依托单位: Nagoya City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2013
• 资助国家: 日本
• 起止时间: 2013-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-25670059/
• 关键词: ケミカルバイオロジー; 酵素阻害剤; 薬学

Peptidyl prolyl isomerase, Pin1, is an enzyme that catalyzes isomerization reaction of phosopho-serine-proline and phospho-threonine-proline amide bond. I planned to develop inhibitors for Pin1 enzyme based on thioamide-containing peptides. Proline thioamide has larger rotation energy for isomerization in comparison with normal proline amide bonds in peptides. Thioamide derivatives of the substrate for Pin1 are expected to slow the reaction of Pin1. I synthesized thioamide version of Pin1 substrate peptide derivatives and evaluate its inhibitory activity for Pin1 enzyme. The synthesized thioamide showed larger inhibitory activity against Pin1 in comparison with the simple substrate competition at the active site.

肽酰脯氨酰异构酶Pin1是一种催化磷酸丝氨酸脯氨酸和磷酸苏氨酸脯氨酸酰胺键异构化的酶。我计划开发基于含硫代酰胺肽的Pin1酶抑制剂。脯氨酸硫代酰胺具有更大的旋转能量的异构化相比，正常的脯氨酸酰胺键的肽。预期Pin1底物的硫代酰胺衍生物会减慢Pin1的反应。我合成了硫代酰胺形式的Pin1底物肽衍生物，并评估其对Pin1酶的抑制活性。合成的硫代酰胺显示出更大的抑制活性对Pin1在活性位点的简单底物竞争相比。