8TCE

Lipoprotein(a) Kringle IV domain 8 - Lp(a) KIV8 in complex with LY3353871

8TCE の概要

• エントリーDOI: 10.2210/pdb8tce/pdb
• 分子名称: Apolipoprotein(a), (2S)-3-phenyl-2-[(3R)-pyrrolidin-3-yl]propanoic acid (3 entities in total)
• 機能のキーワード: complex, inhibitor, ldl, lipid binding protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22234.73

構造登録者

Hendle, J.,Weichert, K.,Sauder, J.M. (登録日: 2023-06-30, 公開日: 2024-05-08, 最終更新日: 2024-10-30)

主引用文献

Diaz, N.,Perez, C.,Escribano, A.M.,Sanz, G.,Priego, J.,Lafuente, C.,Barberis, M.,Calle, L.,Espinosa, J.F.,Priest, B.T.,Zhang, H.Y.,Nosie, A.K.,Haas, J.V.,Cannady, E.,Borel, A.,Schultze, A.E.,Sauder, J.M.,Hendle, J.,Weichert, K.,Nicholls, S.J.,Michael, L.F.
Discovery of potent small-molecule inhibitors of lipoprotein(a) formation.
Nature, 629:945-950, 2024

PubMed 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)). Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (K) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a) (refs. ). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) K7-8. We identify compounds that bind to apo(a) K7-8, 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).

PubMed: 38720069
DOI: 10.1038/s41586-024-07387-z

実験手法

X-RAY DIFFRACTION (1.07 Å)