Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and apolipoprotein(a) (apo(a))^1,2. Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (K_IV) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a) (refs. ^3,4,5,6,7). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) K_IV7–8. We identify compounds that bind to apo(a) K_IV7–8, and, through chemical optimization and further application of multivalency, we create compounds with subnanomolar potency that inhibit the formation of Lp(a). Oral doses of prototype compounds and a potent, multivalent disruptor, LY3473329 (muvalaplin), reduced the levels of Lp(a) in transgenic mice and in cynomolgus monkeys. Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329—which is already in phase 2 studies—as a potent and specific orally administered agent for reducing the levels of Lp(a).

脂蛋白(a) (Lp(a)) 是一种独立的因果心血管危险因素，是一种脂蛋白颗粒，由低密度脂蛋白(LDL) 颗粒和载脂蛋白(a) (apo(a)) 相互作用形成^1,2 . Apo(a) 首先通过 Kringle IV (K _IV ) 7 和 8 结构域与 LDL 上载脂蛋白 B-100 (apoB-100) 的赖氨酸残基结合，然后在 apo(a) 和 apoB-100 之间形成二硫键以产生Lp(a)（参考文献^{3、4、5、6、7}）。在这里，我们证明 Lp(a) 形成的第一步可以通过与 apo(a) K _IV 7-8 的小分子相互作用来抑制。我们鉴定了与 apo(a) K _IV 7-8结合的化合物，并通过化学优化和多价的进一步应用，我们创造了具有亚纳摩尔效力的化合物，可抑制 Lp(a) 的形成。口服剂量的原型化合物和强效多价干扰剂 LY3473329（muvalaplin）可降低转基因小鼠和食蟹猴中的 Lp(a) 水平。尽管多价分子与大鼠纤溶酶原的 Kringle 结构域结合并降低纤溶酶活性，但纤溶酶原序列的物种选择性差异表明，抑制剂分子会降低人类中 Lp(a) 的水平，但不会降低纤溶酶原的水平。这些数据支持 LY3473329 的临床开发（已进入 2 期研究）作为一种有效且特异性的口服药物，用于降低 Lp(a) 水平。