Department of Chemical Pathology bDepartment of Medicine, University of Cape Town, Cape Town, South Africa.
Curr Opin Lipidol. 2012 Dec;23(6):511-7. doi: 10.1097/MOL.0b013e3283587563.
There are now ample data that demonstrate that inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) can safely lower LDL cholesterol synergistically with statins. Considering that PCSK9 was first identified less than a decade ago, the last few years have shown rapid and remarkable advancements in our understanding and knowledge of the structure and function of PCSK9.
Therapeutic developments have not lagged far behind with some monoclonal antibodies currently entering phase III trials. Of the many approaches to PCSK9 inhibition, these compounds are the furthest advanced in their clinical development while small molecule oral inhibitors seem a distant prospect.
This review summarizes the discovery and history of PCSK9 and in particular its mode of action as an inhibitor of the LDL receptor. It also recapitulates key studies that have demonstrated the potential of inhibiting PCSK9 to further decrease LDL-cholesterol levels safely and synergistically with statins. Finally, we review the strategies that are currently in development to inhibit PCSK9, with a special emphasis on the spectacular results from recent phase-I and phase-II clinical trials.
目前有大量数据表明，PCSK9（脯氨酰肽链内切酶/枯草溶菌素蛋白酶 9）抑制剂与他汀类药物联合使用可安全降低 LDL 胆固醇。考虑到 PCSK9 是在不到十年前首次被发现的，过去几年中，我们对 PCSK9 的结构和功能的理解和认识迅速取得了显著进展。
治疗方法的发展也不甘落后，一些单克隆抗体目前正在进入 III 期临床试验。在许多 PCSK9 抑制方法中，这些化合物在临床开发方面处于领先地位，而小分子口服抑制剂似乎还遥遥无期。
本综述总结了 PCSK9 的发现和历史，特别是其作为 LDL 受体抑制剂的作用模式。它还回顾了关键研究，这些研究表明，抑制 PCSK9 与他汀类药物联合使用可安全、协同地进一步降低 LDL 胆固醇水平。最后，我们综述了目前正在开发的抑制 PCSK9 的策略，特别强调了最近 I 期和 II 期临床试验的惊人结果。
