Morpholine-Facilitated Enrichment-Triggered Delivery of Carbon Monoxide to Lysosome: A Feasibility Study

IF 3.3 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Ravi Tripathi, Dongning Liu, Xiaoxiao Yang, Ce Yang, Wen Lu, Qiyue Mao, Binghe Wang
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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.

Abstract Image

morpholine促进富集触发一氧化碳递送到溶酶体:可行性研究
靶向递送一氧化碳(CO)前药具有重要的治疗潜力的各种应用。沿着这条思路,我们开发了一种富集触发释放(ETR)方法,用于在线粒体富集时激活2组分(二烯和亲二烯)CO前药,实现了“一石二鸟”的方法。在此,我们的目标是将应用范围扩大到靶向递送到溶酶体。我们将一个CO前药对,一个二烯和一个亲二烯,以及一个溶酶体靶向部分的啉系在一起。合成了几个类似物来调整二阶速率常数(k2)到一个理想的范围。我们选择了两对具有不同二级速率常数(0.087和0.21 M−1 s−1)的前药,进一步研究了它们的富集和CO释放能力。对于其中一对,LC-MS实验显示,与非靶向对照相比,HeLa细胞中morpholine-conjugated CO前药对富集了13倍。荧光研究表明LysoTracker具有相同的富集和共定位。对于第二对,与morpholine偶联并没有导致溶酶体中富集的改善。这项研究首次证明了以溶酶体为靶点的CO递送。然而,我们的研究结果也注意到啉部分导致溶酶体富集的非普遍性。适度的富集也意味着这种方法可能只适用于靶向递送强效药物。
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来源期刊
Chemical Biology & Drug Design
Chemical Biology & Drug Design 医学-生化与分子生物学
CiteScore
5.10
自引率
3.30%
发文量
164
审稿时长
4.4 months
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.
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