Sandmark, Jenny; Tigerstroem, Anna; Akerud, Tomas; Althage, Magnus; Antonsson, Thomas; Blaho, Stefan; Bodin, Cristian; Bostroem, Jonas; Chen, Yantao; Dahlen, Anders; Eriksson, Per-Olof; Evertsson, Emma; Fex, Tomas; Fjellstroem, Ola; Gustafsson, David; Hersloef, Margareta; Hicks, Ryan; Jarkvist, Emelie; Johansson, Carina; Kalies, Inge; Svalstedt, Birgitta Karlsson; Kartberg, Fredrik; Legnehed, Anne; Martinsson, Sofia; Moberg, Andreas; Ridderstroem, Marianne; Rosengren, Birgitta; Sabirsh, Alan; Thelin, Anders; Vinblad, Johanna; Wellner, Annika U.; Xu, Bingze; Oestlund-Lindqvist, Ann-Margret; Knecht, Wolfgang published the artcile< Identification and analyses of inhibitors targeting apolipoprotein(a) kringle domains KIV-7, KIV-10, and KV provide insight into kringle domain function>, Related Products of 112-63-0, the main research area is preparation inhibitor targeting apolipoprotein kringle domain; Lp(a); X-ray crystallography; apo(a); apolipoprotein; apolipoprotein(a); cardiovascular disease; crystal structure; crystallography; drug design; drug discovery; low-density lipoprotein (LDL); small molecule inhibitor; surface plasmon resonance (SPR).
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-d. lipoprotein (LDL). Many of apo(a)’s potential pathol. 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-mol. 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 mols. that specifically bind to the apo(a) kringle domains KIV-7, KIV-10, and KV. Chem. synthesis yielded compound AZ-05, which bound to KIV-10 with a Kd of 0.8æ¸M 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-mol. ligands at 1.6-2.1 è?resolutions Furthermore, we used these small mols. as chem. 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 pathophysiol. 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-mol. inhibitor targeting the lysine-binding site of KIV-10 can combat the pathophysiol. effects of Lp(a).
Journal of Biological Chemistry published new progress about Apolipoprotein A Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 112-63-0 belongs to class esters-buliding-blocks, and the molecular formula is C19H34O2, Related Products of 112-63-0.
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