 |
PDBsum entry 4ov6
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase/protein binding
|
PDB id
|
|
|
|
4ov6
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Pharmacologic profile of the adnectin bms-962476, A small protein biologic alternative to pcsk9 antibodies for low-Density lipoprotein lowering.
|
|
|
Authors
|
|
T.Mitchell,
G.Chao,
D.Sitkoff,
F.Lo,
H.Monshizadegan,
D.Meyers,
S.Low,
K.Russo,
R.Dibella,
F.Denhez,
M.Gao,
J.Myers,
G.Duke,
M.Witmer,
B.Miao,
S.P.Ho,
J.Khan,
R.A.Parker.
|
|
|
Ref.
|
|
J Pharmacol Exp Ther, 2014,
350,
412-424.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Proprotein convertase subtilisin kexin-9 (PCSK9) is an important pharmacological
target for decreasing low-density lipoprotein (LDL) in cardiovascular disease,
although seemingly inaccessible to small molecule approaches. Compared with
therapeutic IgG antibodies currently in development, targeting circulating PCSK9
with smaller molecular scaffolds could offer different profiles and reduced dose
burdens. This inspired genesis of PCSK9-binding Adnectins, a protein family
derived from human fibronectin-10th-type III-domain and engineered for
high-affinity target binding. BMS-962476, an ∼11-kDa polypeptide conjugated to
polyethylene glycol to enhance pharmacokinetics, binds with subnanomolar
affinity to human. The X-ray cocrystal structure of PCSK9 with a progenitor
Adnectin shows ∼910 Å(2) of PCSK9 surface covered next to the LDL receptor
binding site, largely by residues of a single loop of the Adnectin. In
hypercholesterolemic, overexpressing human PCSK9 transgenic mice, BMS-962476
rapidly lowered cholesterol and free PCSK9 levels. In genomic transgenic mice,
BMS-962476 potently reduced free human PCSK9 (ED50 ∼0.01 mg/kg) followed by
∼2-fold increases in total PCSK9 before return to baseline. Treatment of
cynomolgus monkeys with BMS-962476 rapidly suppressed free PCSK9 >99% and
LDL-cholesterol ∼55% with subsequent 6-fold increase in total PCSK9,
suggesting reduced clearance of circulating complex. Liver sterol response genes
were consequently downregulated, following which LDL and total PCSK9 returned to
baseline. These studies highlight the rapid dynamics of PCSK9 control over LDL
and liver cholesterol metabolism and characterize BMS-962476 as a potent and
efficacious PCSK9 inhibitor.
|
|
|
|
|
|
|
