Identification of a PCSK9-LDLR disruptor peptide with in vivo function
Copyright © 2021 Elsevier Ltd. All rights reserved..
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 1013in vitro-translated macrocyclic peptides to identify high-affinity PCSK9 ligands that utilize a unique, induced-fit pocket and partially disrupt the PCSK9-LDLR interaction. Structure-based design led to molecules with enhanced function and pharmacokinetic properties (e.g., 13PCSK9i). In mice, 13PCSK9i reduces plasma cholesterol levels and increases hepatic LDLR density in a dose-dependent manner. 13PCSK9i functions by a unique, allosteric mechanism and is the smallest molecule identified to date with in vivo PCSK9-LDLR disruptor function.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:29 |
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| Enthalten in: |
Cell chemical biology - 29(2022), 2 vom: 17. Feb., Seite 249-258.e5 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Brousseau, Margaret E [VerfasserIn] |
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| Links: |
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| Themen: |
EC 3.4.21.- |
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| Anmerkungen: |
Date Completed 08.03.2022 Date Revised 08.03.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.chembiol.2021.08.012 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM330890409 |
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| 100 | 1 | |a Brousseau, Margaret E |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Identification of a PCSK9-LDLR disruptor peptide with in vivo function |
| 264 | 1 | |c 2022 | |
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| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 08.03.2022 | ||
| 500 | |a Date Revised 08.03.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 Elsevier Ltd. All rights reserved. | ||
| 520 | |a 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 1013in vitro-translated macrocyclic peptides to identify high-affinity PCSK9 ligands that utilize a unique, induced-fit pocket and partially disrupt the PCSK9-LDLR interaction. Structure-based design led to molecules with enhanced function and pharmacokinetic properties (e.g., 13PCSK9i). In mice, 13PCSK9i reduces plasma cholesterol levels and increases hepatic LDLR density in a dose-dependent manner. 13PCSK9i functions by a unique, allosteric mechanism and is the smallest molecule identified to date with in vivo PCSK9-LDLR disruptor function | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a LDL | |
| 650 | 4 | |a LDL receptor | |
| 650 | 4 | |a PCSK9 | |
| 650 | 4 | |a macrocycle | |
| 650 | 4 | |a protein-protein interaction disruptor | |
| 650 | 4 | |a structure | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Peptides |2 NLM | |
| 650 | 7 | |a Receptors, LDL |2 NLM | |
| 650 | 7 | |a Proprotein Convertase 9 |2 NLM | |
| 650 | 7 | |a EC 3.4.21.- |2 NLM | |
| 700 | 1 | |a Clairmont, Kevin B |e verfasserin |4 aut | |
| 700 | 1 | |a Spraggon, Glen |e verfasserin |4 aut | |
| 700 | 1 | |a Flyer, Alec N |e verfasserin |4 aut | |
| 700 | 1 | |a Golosov, Andrei A |e verfasserin |4 aut | |
| 700 | 1 | |a Grosche, Philipp |e verfasserin |4 aut | |
| 700 | 1 | |a Amin, Jakal |e verfasserin |4 aut | |
| 700 | 1 | |a Andre, Jerome |e verfasserin |4 aut | |
| 700 | 1 | |a Burdick, Debra |e verfasserin |4 aut | |
| 700 | 1 | |a Caplan, Shari |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Guanjing |e verfasserin |4 aut | |
| 700 | 1 | |a Chopra, Raj |e verfasserin |4 aut | |
| 700 | 1 | |a Ames, Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Dubiel, Diana |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Gattlen, Raphael |e verfasserin |4 aut | |
| 700 | 1 | |a Kelly-Sullivan, Dawn |e verfasserin |4 aut | |
| 700 | 1 | |a Koch, Alexander W |e verfasserin |4 aut | |
| 700 | 1 | |a Lewis, Ian |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Jingzhou |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Eugene |e verfasserin |4 aut | |
| 700 | 1 | |a Lubicka, Danuta |e verfasserin |4 aut | |
| 700 | 1 | |a Marzinzik, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Nakajima, Katsumasa |e verfasserin |4 aut | |
| 700 | 1 | |a Nettleton, David |e verfasserin |4 aut | |
| 700 | 1 | |a Ottl, Johannes |e verfasserin |4 aut | |
| 700 | 1 | |a Pan, Meihui |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Tajesh |e verfasserin |4 aut | |
| 700 | 1 | |a Perry, Lauren |e verfasserin |4 aut | |
| 700 | 1 | |a Pickett, Stephanie |e verfasserin |4 aut | |
| 700 | 1 | |a Poirier, Jennifer |e verfasserin |4 aut | |
| 700 | 1 | |a Reid, Patrick C |e verfasserin |4 aut | |
| 700 | 1 | |a Pelle, Xavier |e verfasserin |4 aut | |
| 700 | 1 | |a Seepersaud, Mohindra |e verfasserin |4 aut | |
| 700 | 1 | |a Subramanian, Vanitha |e verfasserin |4 aut | |
| 700 | 1 | |a Vera, Victoria |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Mei |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Lihua |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Qing |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Jinghua |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Guoming |e verfasserin |4 aut | |
| 700 | 1 | |a Monovich, Lauren G |e verfasserin |4 aut | |
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