Ravi Tripathi, Dongning Liu, Xiaoxiao Yang, Ce Yang, Wen Lu, Qiyue Mao, Binghe Wang
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引用次数: 0
Abstract
Targeted delivery of carbon monoxide (CO) prodrugs holds important therapeutic potential for various applications. Along this line, we developed an enrichment-triggered release (ETR) approach for activating 2-component (a diene and a dienophile) CO prodrugs upon enrichment in the mitochondrion, giving a “one stone, two birds” approach. Herein, we aim to broaden the scope of application to targeted delivery to the lysosome. We tethered a CO prodrug pair, a diene and a dienophile, with morpholine, a lysosomal targeting moiety. Several analogs were synthesized to tune the second-order rate constants (k2) to a desirable range. We chose two pairs of the prodrugs with different second-order rate constants (0.087 and 0.21 M−1 s−1) to further study their enrichment and CO release ability. For one pair, LC–MS experiments revealed > 13-fold enrichment of the morpholine-conjugated CO prodrug pair compared to non-targeted controls in HeLa cells. Fluorescence studies demonstrated the same enrichment and co-localization of LysoTracker. For the second pair, conjugation with morpholine did not lead to improved enrichment in the lysosome. This study represents the first demonstration of lysosome-targeted delivery of CO. However, our findings also note the nonuniversal nature for a morpholine moiety to lead to lysosomal enrichment. The modest magnitude of enrichment also means that this method may only be applicable for targeted delivery of a highly potent drug.
期刊介绍:
Chemical Biology & Drug Design is a peer-reviewed scientific journal that is dedicated to the advancement of innovative science, technology and medicine with a focus on the multidisciplinary fields of chemical biology and drug design. It is the aim of Chemical Biology & Drug Design to capture significant research and drug discovery that highlights new concepts, insight and new findings within the scope of chemical biology and drug design.