Identification of a PCSK9-LDLR disruptor peptide with in vivo function.
LDL
LDL receptor
PCSK9
macrocycle
protein-protein interaction disruptor
structure
Journal
Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030
Informations de publication
Date de publication:
17 02 2022
17 02 2022
Historique:
received:
25
01
2021
revised:
13
05
2021
accepted:
27
08
2021
pubmed:
22
9
2021
medline:
9
3
2022
entrez:
21
9
2021
Statut:
ppublish
Résumé
Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting hepatic LDL receptor (LDLR) degradation. Therapeutic antibodies that disrupt PCSK9-LDLR binding reduce LDL-C concentrations and cardiovascular disease risk. The epidermal growth factor precursor homology domain A (EGF-A) of the LDLR serves as a primary contact with PCSK9 via a flat interface, presenting a challenge for identifying small molecule PCSK9-LDLR disruptors. We employ an affinity-based screen of 10
Identifiants
pubmed: 34547225
pii: S2451-9456(21)00401-3
doi: 10.1016/j.chembiol.2021.08.012
pii:
doi:
Substances chimiques
Ligands
0
Peptides
0
Receptors, LDL
0
Proprotein Convertase 9
EC 3.4.21.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
249-258.e5Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests Several authors are past or current employees of Novartis Institutes for BioMedical Research (NIBR), who funded this work. P.C.R. is Chief Scientific Officer at PeptiDream (Tokyo, Japan). Some of the authors (A.N.F., A.A.G., P.G., I.L., E.L., A.M., J.O., T.P., P.C.R., M.S., L.G.M.) have a patent related to this work: WO/2020/110011, cyclic peptides as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for the treatment of metabolic disorders).