Identification and analyses of inhibitors targeting apolipoprotein(a) kringle domains KIV-7, KIV-10, and KV provide insight into kringle domain function

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift


Increased plasma concentrations of lipoprotein(a) (Lp(a)) are associated with an increased risk for cardiovascular disease. Lp(a) is composed of apolipoprotein(a) (apo(a)) covalently bound to apolipoprotein B of low-density lipoprotein (LDL). Many of apo(a)'s potential pathological properties, such as inhibition of plasmin generation, have been attributed to its main structural domains, the kringles, and have been proposed to be mediated by their lysine-binding sites. However, available small-molecule inhibitors, such as lysine analogs, bind unselectively to kringle domains and are therefore unsuitable for functional characterization of specific kringle domains. Here, we discovered small molecules that specifically bind to the apo(a) kringle domains KIV-7, KIV-10, and KV. Chemical synthesis yielded compound AZ-05, which bound to KIV-10 with a Kd of 0.8 μm and exhibited more than 100-fold selectivity for KIV-10, compared with the other kringle domains tested, including plasminogen kringle 1. To better understand and further improve ligand selectivity, we determined the crystal structures of KIV-7, KIV-10, and KV in complex with small-molecule ligands at 1.6-2.1 Å resolutions. Furthermore, we used these small molecules as chemical probes to characterize the roles of the different apo(a) kringle domains in in vitro assays. These assays revealed the assembly of Lp(a) from apo(a) and LDL, as well as potential pathophysiological mechanisms of Lp(a), including (i) binding to fibrin, (ii) stimulation of smooth-muscle cell proliferation, and (iii) stimulation of LDL uptake into differentiated monocytes. Our results indicate that a small-molecule inhibitor targeting the lysine-binding site of KIV-10 can combat the pathophysiological effects of Lp(a).


  • Jenny Sandmark
  • Anna Tigerström
  • Tomas Akerud
  • Magnus Althage
  • Thomas Antonsson
  • Stefan Blaho
  • Cristian Bodin
  • Jonas Boström
  • Yantao Chen
  • Anders Dahlén
  • Per-Olof Eriksson
  • Emma Evertsson
  • Tomas Fex
  • Ola Fjellström
  • David Gustafsson
  • Margareta Herslöf
  • Ryan Hicks
  • Emelie Jarkvist
  • Carina Johansson
  • Inge Kalies
  • Birgitta Karlsson Svalstedt
  • Fredrik Kartberg
  • Anne Legnehed
  • Sofia Martinsson
  • Andreas Moberg
  • Marianne Ridderström
  • Birgitta Rosengren
  • Alan Sabirsh
  • Anders Thelin
  • Johanna Vinblad
  • Annika U Wellner
  • Bingze Xu
  • Ann-Margret Östlund-Lindqvist
Externa organisationer
  • AstraZeneca
Sidor (från-till)5136-5151
TidskriftThe Journal of biological chemistry
Utgåva nummer15
StatusPublished - 2020 apr 10
Peer review utfördJa
Externt publiceradJa