Recent Update on the Development of PCSK9 Inhibitors for Hypercholesterolemia Treatment,Journal of Medicinal Chemistry

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Recent Update on the Development of PCSK9 Inhibitors for Hypercholesterolemia Treatment
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-11-29 , DOI: 10.1021/acs.jmedchem.2c01290
Shakir Ahamad ₁ , Shahnawaz A Bhat ₂

Affiliation

The proprotein convertase subtilisin/kexin-type 9 (PCSK9) binds to low-density lipoprotein receptors (LDLR), thereby trafficking them to lysosomes upon endocytosis and enhancing intracellular degradation to prevent their recycling. As a result, the levels of circulating LDL cholesterol (LDL-C) increase, which is a prominent risk factor for developing atherosclerotic cardiovascular diseases (ASCVD). Thus, PCSK9 has become a promising therapeutic target that offers a fertile testing ground for new drug modalities to regulate plasma LDL-C levels to prevent ASCVD. In this review, we have discussed the role of PCSK9 in lipid metabolism and briefly summarized the current clinical status of modalities targeting PCSK9. In particular, a detailed overview of peptide-based PCSK9 inhibitors is presented, which emphasizes their structural features and design, therapeutic effects on patients, and preclinical cardiovascular disease (CVD) models, along with PCSK9 modulation mechanisms. As a promising alternative to monoclonal antibodies (mAbs) for managing LDL-C, anti-PCSK9 peptides are emerging as a prospective next generation therapy.

中文翻译：

用于高胆固醇血症治疗的 PCSK9 抑制剂的最新进展

前蛋白转化酶枯草杆菌蛋白酶/kexin-9 型 (PCSK9) 与低密度脂蛋白受体 (LDLR) 结合，从而在内吞作用时将其转运至溶酶体，并增强细胞内降解以防止其再循环。结果，循环中的低密度脂蛋白胆固醇（LDL-C）水平升高，这是发生动脉粥样硬化性心血管疾病（ASCVD）的一个重要危险因素。因此，PCSK9 已成为一个有前途的治疗靶点，为调节血浆 LDL-C 水平以预防 ASCVD 的新药物模式提供了肥沃的试验场。在这篇综述中，我们讨论了 PCSK9 在脂质代谢中的作用，并简要总结了针对 PCSK9 的治疗方式的当前临床状况。特别是，详细概述了基于肽的 PCSK9 抑制剂，强调了它们的结构特征和设计，对患者的治疗效果、临床前心血管疾病 (CVD) 模型以及 PCSK9 调节机制。作为治疗 LDL-C 的单克隆抗体 (mAb) 的有前途的替代品，抗 PCSK9 肽正在成为一种有前景的下一代疗法。

更新日期：2022-11-29

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