美国加州大学Taunton Jack团队报道了合成和单分子成像显示抗肿瘤eEF1A拮抗剂SR-A3可立体强化结合动力学。相关研究成果于2022年9月19日发表在国际顶尖学术期刊《自然—化学》。

Ternatin家族环肽通过靶向真核延长因子-1α抑制蛋白质合成。从曲霉中分离出一种潜在相关的细胞毒性天然产物（'A3'），但其11个立体中心中只有4个可以被指定。

该文中，研究人员合成了128种可能的A3差向异构体中的两种SR-A3和SS-A3，并发现合成的SR-A3与天然衍生的A3无法区分。与SS-A3相比，SR-A3表现出更强的停留时间和再结合动力学，如真核延伸因子-1α在体外催化的延伸反应的单分子荧光成像所示。在细胞中还观察到SR-A3中独特的β-羟基立体专一性增加了停留时间。与其作用持续时间延长相一致，在一个侵袭性Myc驱动的小鼠淋巴瘤模型中，每周三次给药SR-A3可减少肿瘤负担并提高生存率。

研究结果证明了SR-A3作为癌症治疗药物的潜力，并举例说明了通过立体特异性侧链羟基化增强环肽结合动力学的进化机制。

附：英文原文

Title: Synthesis and single-molecule imaging reveal stereospecific enhancement of binding kinetics by the antitumour eEF1A antagonist SR-A3

Author: Wang, Hao-Yuan, Yang, Haojun, Holm, Mikael, Tom, Harrison, Oltion, Keely, Al-Khdhairawi, Amjad Ayad Qatran, Weber, Jean-Frdric F., Blanchard, Scott C., Ruggero, Davide, Taunton, Jack

Issue&Volume: 2022-09-19

Abstract: Ternatin-family cyclic peptides inhibit protein synthesis by targeting the eukaryotic elongation factor-1α. A potentially related cytotoxic natural product (‘A3’) was isolated from Aspergillus, but only 4 of its 11 stereocentres could be assigned. Here, we synthesized SR-A3 and SS-A3—two out of 128 possible A3 epimers—and discovered that synthetic SR-A3 is indistinguishable from naturally derived A3. Relative to SS-A3, SR-A3 exhibits an enhanced residence time and rebinding kinetics, as revealed by single-molecule fluorescence imaging of elongation reactions catalysed by eukaryotic elongation factor-1α in vitro. An increased residence time—stereospecifically conferred by the unique β-hydroxyl in SR-A3—was also observed in cells. Consistent with its prolonged duration of action, thrice-weekly dosing with SR-A3 led to a reduced tumour burden and increased survival in an aggressive Myc-driven mouse lymphoma model. Our results demonstrate the potential of SR-A3 as a cancer therapeutic and exemplify an evolutionary mechanism for enhancing cyclic peptide binding kinetics via stereospecific side-chain hydroxylation.

DOI: 10.1038/s41557-022-01039-3

Source: https://www.nature.com/articles/s41557-022-01039-3