文献类型：期刊文献

英文题名：Analysis of Triterpenoid Saponins Reveals Insights into Structural Features Associated with Potent Protein Drug Enhancement Effects

作者：Cao, Xue-Wei[4];Wang, Fu-Jun[1,2,3];Liew, Oi-Wah[5];Lu, Ye-Zhou[4];Zhao, Jian[4]

机构：[1]Zhejiang Fonow Med Co Ltd, Dongyang, Peoples R China;[2]Shanghai R&D Ctr Standardizat Chinese Med, Shanghai, Peoples R China;[3]Shanghai Univ Tradit Chinese Med, Shanghai, Peoples R China;[4]East China Univ Sci & Technol, Shanghai, Peoples R China;[5]Ctr Translat Med, Singapore, Singapore

年份：2020

卷号：17

期号：2

起止页码：683

外文期刊名：MOLECULAR PHARMACEUTICS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000511245300029)】；

基金：The authors declare that they have no conflict of interest regarding the conduct or outcomes of this study. This work was supported by the National Natural Science Foundation of China (grant no. 81571795) and Natural Science Foundation of Shanghai (grant no. 19ZR1457300). The authors are grateful to Ji-Yue Kang and Wei Wang of the Department of Applied Biology for assistance with the preparation of recombinant proteins. The authors also thank Ting Wu and Bo-Hao Yu at Research Center of Analysis and Test for help on confocal microscopy. The authors are also grateful to Li Zhou of the State Key Laboratory of Bioreactor Engineering for assistance with flow cytometry analyses.

语种：英文

外文关键词：saponins; endosomal escape enhancers (EEEs); glycosylated triterpenoid; ribosome-inactivating proteins (RIPS); cytosolic drug delivery; drug release

摘要：Plant-based saponins are amphipathic glycosides composed of a hydrophobic aglycone backbone covalently bound to one or more hydrophilic sugar moieties. Recently, the endosomal escape activity of triterpenoid saponins has been investigated as a potentially powerful tool for improved cytosolic penetration of protein drugs internalized by endocytic uptake, thereby greatly enhancing their pharmacological effects. However, only a few saponins have been studied, and the paucity in understanding the structure activity relationship of saponins imposes significant limitations on their applications. To address this knowledge gap, 12 triterpenoid saponins with diverse structural side chains were screened for their utility as endosomolytic agents. These compounds were used in combination with a toxin (MAP30-HBP) comprising a type I ribosome-inactivating protein fused to a cell-penetrating peptide. Suitability of saponins as endosomolytic agents was assessed on the basis of cytotoxicity, endosomal escape promotion, and synergistic effects on toxins. Five saponins showed strong endosomal escape activity, enhancing MAP30-HBP cytotoxicity by more than 10(6) to 10(9) folds. These saponins also enhanced the apoptotic effect of MAP30-HBP in a pH-dependent manner. Additionally, growth inhibition of MAP30-HBP-treated SMMC-7721 cells was greater than that of similarly treated HeLa cells, suggesting that saponin-mediated endosomolytic effect is likely to be cell-specific. Furthermore, the structural features and hydrophobicity of the sugar side chains were analyzed to draw correlations with endosomal escape activity and derive predictive rules, thus providing new insights into structure-activity relationships of saponins. This study revealed new saponins that can potentially be exploited as efficient cytosolic delivery reagents for improved therapeutic drug effects.