美国礼来研究实验室Laura F. Michael团队发现脂蛋白(a)形成的强效小分子抑制剂。相关论文于2024年5月8日在线发表于国际学术期刊《自然》。
研究人员表示,脂蛋白(a)(Lp(a))是一种独立的心血管风险因子,是由低密度脂蛋白(LDL)颗粒和载脂蛋白(a)(apo(a))相互作用形成的脂蛋白颗粒。apo(a)首先通过Kringle IV(KIV)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,然后载脂蛋白(a)和载脂蛋白B-100之间形成二硫键,生成Lp(a)。
研究人员展示了可以通过小分子与apo(a) KIV7-8的相互作用来抑制Lp(a)形成的第一步。研究人员发现了能与apo(a) KIV7-8结合的化合物,通过化学优化和进一步应用多价性,研究人员创造出了具有亚纳摩尔效力的化合物,可抑制Lp(a)的形成。口服原型化合物和一种强效多价干扰素LY3473329(muvalaplin)可降低转基因小鼠和猴体内的Lp(a)水平。
虽然多价分子能与大鼠纤溶酶原的Kringle结构域结合并降低纤溶酶原的活性,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Lp(a)的水平,但不会降低纤溶酶原的水平。这些数据支持了LY3473329的临床开发,目前该药已进入2期研究,这是一种降低Lp(a)水平的强效特异性口服药物。
附:英文原文
Title: Discovery of potent small-molecule inhibitors of lipoprotein(a) formation
Author: Diaz, Nuria, Perez, Carlos, Escribano, Ana Maria, Sanz, Gema, Priego, Julian, Lafuente, Celia, Barberis, Mario, Calle, Luis, Espinosa, Juan Felix, Priest, Birgit T., Zhang, Hong Y., Nosie, Amanda K., Haas, Joseph V., Cannady, Ellen, Borel, Anthony, Schultze, Albert E., Sauder, J. Michael, Hendle, Jrg, Weichert, Ken, Nicholls, Stephen J., Michael, Laura F.
Issue&Volume: 2024-05-08
Abstract: 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 (KIV) 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) KIV7–8. We identify compounds that bind to apo(a) KIV7–8, 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).
DOI: 10.1038/s41586-024-07387-z
Source: https://www.nature.com/articles/s41586-024-07387-z
Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html