Zong Lili, Bartolami Eline, Abegg Daniel, Adibekian Alexander, Sakai Naomi, Matile Stefan
Department of Organic Chemistry, University of Geneva, CH-1211 Geneva, Switzerland.
ACS Cent Sci. 2017 May 24;3(5):449-453. doi: 10.1021/acscentsci.7b00080. Epub 2017 Apr 6.
The disulfide dihedral angle in epidithiodiketopiperazines (ETPs) is near 0°. Application of this highest possible ring tension to strain-promoted thiol-mediated uptake results in efficient delivery to the cytosol and nucleus. Compared to the previous best asparagusic acid (AspA), ring-opening disulfide exchange with ETPs occurs more efficiently even with nonactivated thiols, and the resulting thiols exchange rapidly with nonactivated disulfides. ETP-mediated cellular uptake is more than 20 times more efficient compared to AspA, occurs without endosomal capture, depends on temperature, and is "unstoppable" by inhibitors of endocytosis and conventional thiol-mediated uptake, including siRNA against the transferrin receptor. These results suggest that ETP-mediated uptake not only maximizes delivery to the cytosol and nucleus but also opens the door to a new multitarget hopping mode of action.
环二硫代二酮哌嗪（ETP）中的二硫键二面角接近0°。将这种尽可能高的环张力应用于应变促进的硫醇介导的摄取，可实现向细胞质和细胞核的高效递送。与之前效果最佳的天冬氨酸（AspA）相比，即使与未活化的硫醇发生开环二硫键交换，ETP也更高效，并且生成的硫醇能与未活化的二硫键快速交换。与AspA相比，ETP介导的细胞摄取效率高出20倍以上，无需内体捕获，依赖于温度，并且不受内吞作用抑制剂和传统硫醇介导摄取抑制剂的影响，包括针对转铁蛋白受体的小干扰RNA。这些结果表明，ETP介导的摄取不仅能最大程度地递送至细胞质和细胞核，还为一种新的多靶点跳跃作用模式打开了大门。
