Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting hepatic LDL receptor (LDLR) degradation. Therapeutic antibodies that disrupt PCSK9-LDLR binding reduce LDL-C concentrations and cardiovascular disease risk. The epidermal growth factor precursor homology domain A (EGF-A) of the LDLR serves as a primary contact with PCSK9 via a flat interface, presenting a challenge for identifying small molecule PCSK9-LDLR disruptors. We employ an affinity-based screen of 10¹³ in vitro-translated macrocyclic peptides to identify high-affinity PCSK9 ligands that utilize a unique, induced-fit pocket and partially disrupt the PCSK9-LDLR interaction. Structure-based design led to molecules with enhanced function and pharmacokinetic properties (e.g., ₁₃PCSK9i). In mice, ₁₃PCSK9i reduces plasma cholesterol levels and increases hepatic LDLR density in a dose-dependent manner. ₁₃PCSK9i functions by a unique, allosteric mechanism and is the smallest molecule identified to date with in vivo PCSK9-LDLR disruptor function.

前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型 (PCSK9) 通过促进肝 LDL 受体 (LDLR) 降解来调节血浆低密度脂蛋白胆固醇 (LDL-C) 水平。破坏 PCSK9-LDLR 结合的治疗性抗体可降低 LDL-C 浓度和心血管疾病风险。LDLR 的表皮生长因子前体同源结构域 A (EGF-A) 通过平面界面作为与 PCSK9 的主要接触，对识别小分子 PCSK9-LDLR 干扰物提出了挑战。我们在体外采用基于亲和力的 10 ^13筛选 -翻译的大环肽以识别高亲和力的 PCSK9 配体，该配体利用独特的诱导贴合口袋并部分破坏 PCSK9-LDLR 相互作用。基于结构的设计导致分子具有增强的功能和药代动力学特性（例如，₁₃ PCSK9i）。在小鼠中，₁₃ PCSK9i以剂量依赖性方式降低血浆胆固醇水平并增加肝脏 LDLR 密度。₁₃ PCSK9i通过独特的变构机制发挥作用，是迄今为止鉴定的具有体内PCSK9-LDLR 破坏功能的最小分子。