人参中PD-1小分子抑制剂的筛选及活性验证

Identification of PD-1 small molecule inhibitors and validation in Panax ginseng

近年来,肿瘤免疫疗法取得了巨大的成功,美国FDA批准了多种PD-1/PD-L1(programmed death-1/programmed death-ligand 1)抗体药物用于晚期恶性肿瘤治疗。然而,抗体药物作为生物大分子具有成本高、给药方式单一和较强的免疫不良反应等缺点,因此具有较低免疫风险和更好修饰性的小分子抑制剂成为值得研究的方向。天然产物中蕴涵有丰富的小分子化合物,而目前关于天然产物中PD-1小分子抑制剂的研究却鲜有报道。因此本研究以中药材人参为研究对象,通过液质联用的方法从中鉴定了9个皂苷类成分,并使用表面等离子共振(SPR)技术从中筛选出了3个具有PD-1结合活性的人参皂苷类化合物。最后使用细胞药理学方法对其中代表性化合物人参皂苷Rg1进行了PD-1/PD-L1抑制活性验证。本研究为天然产物中免疫信号通路抑制剂的研究提供了参考。

Tumor immune therapy has been remarkably successful in recent years and several kinds of PD-1/PD-L1(programmed death-1/programmed death-ligand 1)antibody drugs have been approved by the FDA for treatment of advanced malignant neoplasms.However,as biomacromolecules these antibody drugs have certain drawbacks such as high cost,injection-only administration and immunogenicity;thus,we turned to small molecules that have lower immune risks and better modifiability.Considering the structural diversity of natural products,we chose to investigate the active components in Panax ginseng,a famous and highly valued traditional Chinese medicine.Nine compounds were separated and identified in this research using a HPLC-coupled MS system,and3 PD-1 binding compounds were identified using the SPR method.The PD-1/PD-L1 inhibitory ability of ginsenoside Rg1,as a representative ginsenoside,was verified by cytopharmacological methods.This research provides a new method for the identification of immune blockade inhibitors in natural products.