Singh Vaibhav Pal, Hirose Shuhei, Takemoto Misao, Farrag Asmaa M A S, Sato Shin-Ichi, Honjo Tasuku, Chamoto Kenji, Uesugi Motonari
Division of Biochemistry, Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.
Graduate School of Medicine, Kyoto University, Kyoto, Kyoto 606-8501, Japan.
J Am Chem Soc. 2024 Jun 7. doi: 10.1021/jacs.3c14615.
Cancer immune therapies, particularly programmed cell death protein 1 (PD-1) blockade immunotherapy, falter in aged individuals due to compromised T-cell immunity. Spermidine, a biogenic polyamine that declines along with aging, shows promise in restoring antitumor immunity by enhancing mitochondrial fatty acid oxidation (FAO). Herein, we report a spermidine-based chemoproteomic probe (probe ) that enables profiling of spermidine-binding proteins and screening for small-molecule enhancers of mitochondrial FAO. Chemoproteomic profiling by the probe revealed 140 proteins engaged in cellular interaction with spermidine, with a significant majority being mitochondrial proteins. Hydroxyl coenzyme A (CoA) dehydrogenase subunits α (HADHA) and other lipid metabolism-linked proteins are among the mitochondrial proteins that have attracted considerable interest. Screening spermidine analogs with the probe led to the discovery of compound , which interacts with these lipid metabolism-linked proteins and activates HADHA. This simple and biostable synthetic compound we named "spermimic" mirrors spermidine's ability to enhance mitochondrial bioenergetics and displays similar effectiveness in augmenting PD-1 blockade therapy in mice. This study lays the foundation for developing small-molecule activators of antitumor immunity, offering potential in combination cancer immunotherapy.
癌症免疫疗法，尤其是程序性细胞死亡蛋白1（PD-1）阻断免疫疗法，在老年个体中因T细胞免疫功能受损而效果不佳。亚精胺是一种随着衰老而减少的生物源多胺，在通过增强线粒体脂肪酸氧化（FAO）恢复抗肿瘤免疫方面显示出前景。在此，我们报告了一种基于亚精胺的化学蛋白质组学探针（探针 ），它能够对亚精胺结合蛋白进行分析，并筛选线粒体FAO的小分子增强剂。该探针进行的化学蛋白质组学分析揭示了140种与亚精胺发生细胞相互作用的蛋白质，其中绝大多数是线粒体蛋白。羟基辅酶A（CoA）脱氢酶亚基α（HADHA）和其他与脂质代谢相关的蛋白质是备受关注的线粒体蛋白。用该探针筛选亚精胺类似物导致发现了化合物 ，它与这些脂质代谢相关蛋白相互作用并激活HADHA。我们将这种简单且生物稳定的合成化合物命名为“精子模拟物”，它反映了亚精胺增强线粒体生物能量学的能力，并且在增强小鼠的PD-1阻断疗法方面显示出类似的效果。这项研究为开发抗肿瘤免疫的小分子激活剂奠定了基础，在联合癌症免疫疗法中具有潜力。
