Discovery of potent small-molecule inhibitors of lipoprotein(a) formation.

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 (K_IV) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a) (refs. ^3-7). 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 form

SUBMITTER: Diaz N 

PROVIDER: S-EPMC11111404 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature