Shi Xiaojing, Zhang Xiao-Nan, Chen Jingwen, Cheng Qinqin, Pei Hua, Louie Stan G, Zhang Yong
Department of Pharmacology and Pharmaceutical Sciences , School of Pharmacy , University of Southern California , Los Angeles , CA 90089 , USA.
Titus Family Department of Clinical Pharmacy , School of Pharmacy , University of Southern California , Los Angeles , CA 90089 , USA.
Chem Sci. 2020 Aug 17;11(34):9303-9308. doi: 10.1039/d0sc01795g. eCollection 2020 Sep 14.
Protein poly-ADP-ribosylation (PARylation) plays vital roles in many aspects of physiology and pathophysiology. This posttranslational modification is catalyzed by poly-ADP-ribose polymerases (PARPs) through additions of ADP-ribose from nicotinamide adenine dinucleotide (NAD) to protein residues, forming linear or branched poly-ADP-ribose (PAR) polymers. In this study, we explored a new concept of utilizing functionalized PAR polymers for targeted drug delivery. This was achieved by rapid and efficient generation of auto-PARylated PARP1 with 3'-azido ADP-riboses and subsequent conjugations of anti-human epidermal growth factor receptor 2 (HER2) antibodies and monomethyl auristatin F (MMAF) payloads. This designed PARylated PARP1-antibody-MMAF conjugate could potently kill HER2-expressing cancer cells in high specificity. This proof-of-principle work demonstrates the feasibility of production of PAR polymer-based antibody-drug conjugate and its application in targeted delivery. The PAR polymer-based conjugates may lead to new types of therapeutics with potentially improved physicochemical and pharmacological properties.
蛋白质多聚-ADP-核糖基化（PARylation）在生理和病理生理的许多方面发挥着至关重要的作用。这种翻译后修饰由多聚-ADP-核糖聚合酶（PARPs）催化，通过将烟酰胺腺嘌呤二核苷酸（NAD）中的ADP-核糖添加到蛋白质残基上，形成线性或分支的多聚-ADP-核糖（PAR）聚合物。在本研究中，我们探索了利用功能化PAR聚合物进行靶向药物递送的新概念。这是通过用3'-叠氮基ADP-核糖快速高效地生成自动PAR化的PARP1，随后将抗人表皮生长因子受体2（HER2）抗体和单甲基澳瑞他汀F（MMAF）有效载荷进行偶联来实现的。这种设计的PAR化PARP1-抗体-MMAF偶联物能够以高特异性有效杀死表达HER2的癌细胞。这项原理验证工作证明了基于PAR聚合物的抗体-药物偶联物的生产及其在靶向递送中的应用的可行性。基于PAR聚合物的偶联物可能会带来具有潜在改善的物理化学和药理学性质的新型治疗方法。
