Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California 90089, United States.
Department of Chemistry, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California 90089, United States.
Biomacromolecules. 2022 Dec 12;23(12):5267-5272. doi: 10.1021/acs.biomac.2c01090. Epub 2022 Nov 9.
Poly-ADP-ribose (PAR) is a naturally occurring form of polymers synthesized through enzymatic reactions catalyzed by poly(ADP-ribose) polymerases (PARPs). It is known for regulating various important cellular signaling pathways and processes. As a water soluble and biocompatible type of polymer, PAR may hold promise for safe and efficient delivery of therapeutics. To explore the therapeutic potential of PAR polymers, we herein generate PAR polymers conjugated with human granulocyte colony-stimulating factor (GCSF) protein by harnessing human PARP1-catalyzed auto-poly-ADP-ribosylation and a clickable analogue of nicotinamide adenine dinucleotide (NAD). The resulting PAR polymer-based conjugate with multivalent GCSF ligands exhibits a potent cell proliferative activity. Notably, mice treated with a single dose of the PAR polymer-GCSF conjugate show sustained high levels of neutrophil in blood for 11 days, demonstrating excellent efficacy. Functionalized PAR polymers may provide new scaffolds for conjugating with therapeutic proteins or peptides toward improved pharmacological activities.
多聚 ADP 核糖 (PAR) 是一种通过多聚 ADP 核糖聚合酶 (PARPs) 催化的酶促反应合成的天然存在的聚合物形式。它已知可调节各种重要的细胞信号通路和过程。作为一种水溶性和生物相容性的聚合物，PAR 可能有望实现治疗药物的安全有效递送。为了探索 PAR 聚合物的治疗潜力，我们利用人 PARP1 催化的自动聚 ADP-核糖基化和烟酸腺嘌呤二核苷酸 (NAD) 的可点击类似物，生成与人类粒细胞集落刺激因子 (GCSF) 蛋白偶联的 PAR 聚合物。所得的具有多价 GCSF 配体的 PAR 聚合物缀合物表现出强大的细胞增殖活性。值得注意的是，单次给予 PAR 聚合物-GCSF 缀合物的小鼠在 11 天内血液中的中性粒细胞持续保持高水平，显示出优异的疗效。功能化的 PAR 聚合物可为与治疗性蛋白或肽缀合提供新的支架，以提高药理学活性。
