Department of Organic Chemistry, University of Geneva, Quai Ernest-Ansermet 30, 1211, Geneva, Switzerland.
Chembiochem. 2021 Jan 5;22(1):253-259. doi: 10.1002/cbic.202000630. Epub 2020 Nov 6.
Monomeric cyclic oligochalcogenides (COCs) are emerging as attractive transporters to deliver substrates of interest into the cytosol through thiol-mediated uptake. The objective of this study was to explore COC oligomers. We report a systematic evaluation of monomers, dimers, and trimers of asparagusic, lipoic, and diselenolipoic acid as well as their supramolecular monomers, dimers, trimers, and tetramers. COC dimers were more than twice as active as the monomers on both the covalent and noncovalent levels, whereas COC trimers were not much better than dimers. These trends might suggest that thiol-mediated uptake of COCs is synergistic over both short and long distances, that is, it involves more than two COCs and more than one membrane protein, although other interpretations cannot be excluded at this level of complexity. These results thus provide attractive perspectives for structural evolution as well as imminent use in practice. Moreover, they validate automated HC-CAPA as an invaluable method to collect comprehensive data on cytosolic delivery within a reasonable time at a level of confidence that is otherwise inconceivable.
单体环状寡 chalcogenides（COCs）作为一种有吸引力的转运体，通过硫醇介导的摄取将感兴趣的底物递送到细胞质中。本研究的目的是探索 COC 低聚物。我们报告了对天门冬氨酸、硫辛酸和二硒代硫辛酸的单体、二聚体和三聚体以及它们的超分子单体、二聚体、三聚体和四聚体的系统评估。在共价和非共价水平上，COC 二聚体的活性均是单体的两倍以上，而 COC 三聚体的活性与二聚体相差不大。这些趋势可能表明，COC 的硫醇介导摄取在短距离和长距离上都是协同的，也就是说，它涉及两个以上的 COC 和一个以上的膜蛋白，尽管在这种复杂程度下，不能排除其他解释。这些结果为结构进化以及即将在实践中的应用提供了有吸引力的前景。此外，它们验证了自动化 HC-CAPA 作为一种非常宝贵的方法，可以在合理的时间内以否则难以想象的置信水平收集细胞质内递送的综合数据。
