An Chae-Yeong, Son Min-Gyung, Chin Young-Won
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
ACS Omega. 2023 Aug 25;8(36):32804-32816. doi: 10.1021/acsomega.3c03873. eCollection 2023 Sep 12.
Cholesterol is one of the primary causes of cardiovascular disease. Investigating and developing potential drugs to effectively treat hypercholesterolemia are therefore of critical importance. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been developed to lower the levels of low-density lipoprotein cholesterol in patients with hypercholesterolemia. In this study, we aimed to identify compounds that inhibit the PCSK9 mRNA expression and secretion. The bioassay-guided investigation of seeds utilizing a PCSK9 mRNA expression monitoring assay yielded the isolation and identification of seven new compounds. Among these were three acyclic triterpenoids (, an acyclic sesquiterpenoid (, one arylpentanoid (), and two diarylheptanoids ( and ), alongside 10 known compounds. The structures of these compounds were determined using nuclear magnetic resonance (NMR) spectroscopy, vibrational circular dichroism (VCD), and electronic circular dichroism (ECD). The absolute configurations of compounds and were identified by comparing the calculated and experimental VCD data as the ECD method was unable to distinguish the diastereomers. All the isolated compounds were evaluated for their regulatory effects on the low-density lipoprotein receptor (LDLR) and PCSK9 mRNA expression, as well as PCSK9 secretion. Of the tested compounds, two of the acyclic triterpenoids ( and demonstrated potent effects in downregulating PCSK9 at both the mRNA and protein levels, compared with the positive control (berberine chloride). Additionally, compound inhibited PCSK9 secretion to a level comparable to that of berberine chloride. This study identifies compounds that inhibit PCSK9 mRNA expression and secretion, offering significant contributions to the development of novel drugs for the effective treatment of hypercholesterolemia..
胆固醇是心血管疾病的主要病因之一。因此，研究和开发有效治疗高胆固醇血症的潜在药物至关重要。前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）抑制剂已被开发用于降低高胆固醇血症患者的低密度脂蛋白胆固醇水平。在本研究中，我们旨在鉴定抑制PCSK9 mRNA表达和分泌的化合物。利用PCSK9 mRNA表达监测试验对种子进行生物测定指导的研究，分离并鉴定出7种新化合物。其中包括三种无环三萜类化合物（，一种无环倍半萜类化合物（，一种芳基戊烷类化合物（），以及两种二芳基庚烷类化合物（和），还有10种已知化合物。这些化合物的结构通过核磁共振（NMR）光谱、振动圆二色性（VCD）和电子圆二色性（ECD）确定。由于ECD方法无法区分非对映异构体，通过比较计算和实验VCD数据确定了化合物和的绝对构型。所有分离出的化合物均评估了其对低密度脂蛋白受体（LDLR）和PCSK9 mRNA表达以及PCSK9分泌的调节作用。在测试的化合物中，与阳性对照（氯化小檗碱）相比，两种无环三萜类化合物（和在mRNA和蛋白质水平上均显示出对PCSK9的有效下调作用。此外，化合物抑制PCSK9分泌的水平与氯化小檗碱相当。本研究鉴定出抑制PCSK9 mRNA表达和分泌的化合物，为有效治疗高胆固醇血症的新型药物开发做出了重大贡献。
