Department of Chemistry, Brandeis University 415, Waltham, MA 02454, USA.
Angew Chem Int Ed Engl. 2023 Sep 4;62(36):e202308022. doi: 10.1002/anie.202308022. Epub 2023 Jul 31.
Rapid cellular uptake of synthetic molecules remains a challenge, and the motif frequently employed to generate prodrugs, succinic ester, unfortunately lowers the efficacy of the desired drugs due to their slow ester hydrolysis and low cell entry. Here we show that succinic ester-containing diglycine drastically boosts the cellular uptake of supramolecular assemblies or prodrugs. Specifically, autohydrolysis of the diglycine-activated succinic esters turns the nanofibers of the conjugates of succinic ester and self-assembling motif into nanoparticles for fast cellular uptake. The autohydrolysis of diglycine-activated succinic esters and drug conjugates also restores the efficacy of the drugs. 2D nuclear magnetic resonance (NMR) suggests that a "U-turn" of diglycine favors intramolecular hydrolysis of diglycine-activated succinic esters to promote autohydrolysis. As an example of rapid autohydrolysis of diglycine-activated succinic esters for instant cellular uptake, this work illustrates a nonenzymatic bond cleavage approach to develop effective therapeutics for intracellular targeting.
快速的细胞摄取仍然是一个挑战，而常用于生成前药的琥珀酸酯由于其缓慢的酯水解和低细胞进入，不幸地降低了所需药物的功效。在这里，我们表明含琥珀酸酯的二肽可大大提高超分子组装体或前药的细胞摄取率。具体来说，二肽激活的琥珀酸酯的自动水解将琥珀酸酯和自组装基序的缀合物的纳米纤维转化为用于快速细胞摄取的纳米颗粒。二肽激活的琥珀酸酯和药物缀合物的自动水解也恢复了药物的功效。二维核磁共振（NMR）表明二肽的“U 型转弯”有利于二肽激活的琥珀酸酯的分子内水解，以促进自动水解。作为二肽激活的琥珀酸酯快速自动水解用于即时细胞摄取的一个例子，这项工作说明了一种非酶促键断裂方法，用于开发针对细胞内靶向的有效治疗方法。
