Identification of a PCSK9-LDLR disruptor peptide with in vivo function

被引：32

作者：

Brousseau, Margaret E. ^{[1
]}

Clairmont, Kevin B. ^{[1
]}

Spraggon, Glen ^{[2
]}

Flyer, Alec N. ^{[1
]}

Golosov, Andrei A. ^{[1
]}

Grosche, Philipp ^{[3
]}

Amin, Jakal ^{[1
]}

Andre, Jerome ^{[3
]}

Burdick, Debra ^{[1
]}

Caplan, Shari ^{[1
]}

Chen, Guanjing ^{[1
]}

Chopra, Raj ^{[1
]}

Ames, Lisa ^{[1
]}

Dubiel, Diana ^{[1
]}

Fan, Li ^{[1
]}

Gattlen, Raphael ^{[3
]}

Kelly-Sullivan, Dawn ^{[1
]}

Koch, Alexander W. ^{[1
]}

Lewis, Ian ^{[3
]}

Li, Jingzhou ^{[1
]}

Liu, Eugene ^{[1
]}

Lubicka, Danuta ^{[1
]}

Marzinzik, Andreas ^{[3
]}

Nakajima, Katsumasa ^{[1
]}

Nettleton, David ^{[1
]}

Ottl, Johannes ^{[3
]}

Pan, Meihui ^{[1
]}

Patel, Tajesh ^{[1
]}

Perry, Lauren ^{[1
]}

Pickett, Stephanie ^{[3
]}

Poirier, Jennifer ^{[1
]}

Reid, Patrick C. ^{[4
]}

Pelle, Xavier ^{[3
]}

Seepersaud, Mohindra ^{[1
]}

Subramanian, Vanitha ^{[1
]}

Vera, Victoria ^{[1
]}

Xu, Mei ^{[1
]}

Yang, Lihua ^{[1
]}

Yang, Qing ^{[1
]}

Yu, Jinghua ^{[1
]}

Zhu, Guoming ^{[1
]}

Monovich, Lauren G. ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, 22 Windsor St & 181 Massachusetts Ave, Cambridge, MA 02139 USA

[2] Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA

[3] Novartis Inst BioMed Res, Fabrikstr 2,Novartis Campus, CH-4056 Basel, Switzerland

[4] PeptiDream Inc, Meguro Ku, KOL Bldg,Room 405,4-6-1 Komaba, Tokyo 1538904, Japan

来源：

CELL CHEMICAL BIOLOGY | 2022年 / 29卷 / 02期

关键词：

SMALL-MOLECULE INHIBITORS; FACTOR-LIKE REPEAT; CRYSTAL-STRUCTURE; ANNEXIN A2; PROTEIN; DESIGN; BINDING; ANTIBODIES; DISPLAY; SITE;

D O I：

10.1016/j.chembiol.2021.08.012

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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(13) in 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., (13)PCSK9i). In mice,(13)PCSK9i reduces plasma cholesterol levels and increases hepatic LDLR density in a dose-dependent manner. (13)PCSK9i functions by a unique, allosteric mechanism and is the smallest molecule identified to date with in vivo PCSK9-LDLR disruptor function.

引用

页码：249 / +

页数：16

共 49 条

[1] Abdel-Meguid S.S., 2017, ANTIPROPROTEIN CONVE
[2] Mutations in PCSK9 cause autosomal dominant hypercholesterolemia
Abifadel, M
Varret, M
Rabès, JP
Allard, D
Ouguerram, K
Devillers, M
Cruaud, C
Benjannet, S
Wickham, L
Erlich, D
Derré, A
Villéger, L
Farnier, M
Beucler, I
Bruckert, E
Chambaz, J
Chanu, B
Lecerf, JM
Luc, G
Moulin, P
Weissenbach, J
Prat, A
Krempf, M
Junien, C
Seidah, NG
Boileau, C
[J]. NATURE GENETICS, 2003, 34 (02) : 154 - 156
[3] LDL-R promoting activity of peptides derived from human PCSK9 catalytic domain (153-421): Design, synthesis and biochemical evaluation
Alghamdi, Rasha H.
O'Reilly, Paul
Lu, Chunyu
Gomes, James
Lagace, Thomas A.
Basak, Ajoy
[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2015, 92 : 890 - 907
[4] Series of Novel and Highly Potent Cyclic Peptide PCSK9 Inhibitors Derived from an mRNA Display Screen and Optimized via Structure-Based Design
Alleyne, Candice
Amin, Rupesh P.
Bhatt, Bhavana
Bianchi, Elisabetta
Blain, J. Craig
Boyer, Nicolas
Branca, Danila
Embrey, Mark W.
Ha, Sookhee N.
Jette, Kelli
Johns, Douglas G.
Kerekes, Angela D.
Koeplinger, Kenneth A.
LaPlaca, Derek
Li, Nianyu
Murphy, Beth
Orth, Peter
Ricardo, Alonso
Salowe, Scott
Seyb, Kathleen
Shahripour, Aurash
Stringer, Joseph R.
Sun, Yili
Tracy, Rodger
Wu, Chengwei
Xiong, Yusheng
Youm, Hyewon
Zokian, Hratch J.
Tucker, Thomas J.
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2020, 63 (22) : 13796 - 13824
[5] A RECEPTOR-MEDIATED PATHWAY FOR CHOLESTEROL HOMEOSTASIS
BROWN, MS
GOLDSTEIN, JL
[J]. SCIENCE, 1986, 232 (4746) : 34 - 47
[6] Design of Organo-Peptides As Bipartite PCSK9 Antagonists
Burdick, Daniel J.
Skelton, Nicholas J.
Ultsch, Mark
Beresini, Maureen H.
Eigenbrot, Charles
Li, Wei
Zhang, Yingnan
Huy Nguyen
Kong-Beltran, Monica
Quinn, John G.
Kirchhofer, Daniel
[J]. ACS CHEMICAL BIOLOGY, 2020, 15 (02) : 425 - 436
[7] Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia
Cunningham, David
Danley, Dennis E.
Geoghegan, Kieran F.
Griffor, Matthew C.
Hawkins, Julie L.
Subashi, Timothy A.
Varghese, Alison H.
Ammirati, Mark J.
Culp, Jeffrey S.
Hoth, Lise R.
Mansour, Mahmoud N.
McGrath, Katherine M.
Seddon, Andrew P.
Shenolikar, Shirish
Stutzman-Engwall, Kim J.
Warren, Laurie C.
Xia, Donghui
Qiu, Xiayang
[J]. NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2007, 14 (05) : 413 - 419
[8] Coot:: model-building tools for molecular graphics
Emsley, P
Cowtan, K
[J]. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2004, 60 : 2126 - 2132
[9] A small molecule inhibitor of PCSK9 that antagonizes LDL receptor binding via interaction with a cryptic PCSK9 binding groove
Evison, Benny J.
Palmer, James T.
Lambert, Gilles
Treutlein, Herbert
Zeng, Jun
Nativel, Brice
Chemello, Kevin
Zhu, Qing
Wang, Jie
Teng, Yanfen
Tang, Wei
Xu, Yanfeng
Rathi, Anuj Kumar
Kumar, Sanjay
Suchowerska, Alexandra K.
Parmar, Jasneet
Dixon, Ian
Kelly, Graham E.
Bonnar, James
[J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2020, 28 (06)
[10] Design of Thioether Cyclic Peptide Scaffolds with Passive Permeability and Oral Exposure
Golosov, Andrei A.
Flyer, Alec N.
Amin, Jakal
Babu, Charles
Gampe, Christian
Li, Jingzhou
Liu, Eugene
Nakajima, Katsumasa
Nettleton, David
Patel, Tajesh J.
Reid, Patrick C.
Yang, Lihua
Monovich, Lauren G.
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2021, 64 (05) : 2622 - 2633

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