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Inhibition of low-density lipoprotein receptor degradation with a cyclic peptide that disrupts the homodimerization of IDOL E3 ubiquitin ligase

Inhibition of low-density lipoprotein receptor degradation with a cyclic peptide that disrupts the homodimerization of IDOL E3 ubiquitin ligase
Inhibition of low-density lipoprotein receptor degradation with a cyclic peptide that disrupts the homodimerization of IDOL E3 ubiquitin ligase
Cellular uptake of circulating cholesterol occurs via the low density lipoprotein receptor (LDLR). The E3 ubiquitin ligase IDOL is a mediator of LDLR degradation, with IDOL homodimerization thought to be required for its activity. To probe the possibility of modulating LDLR levels with an inhibitor of IDOL homodimerization, we screened a SICLOPPS library of 3.2 million cyclic peptides for compounds that disrupt this protein-protein interaction. We identified cyclo-CFFLYT as the lead inhibitor, and improved its activity through the incorporation of non-natural amino acids. The activity of the optimized cyclic peptide was assessed in hepatic cells, with a dose-dependent increase in LDLR levels observed in the presence of our IDOL homodimerization inhibitor.
SICLOPPS, IDOL, cyclic peptide, LDLR, protein-protein interaction networks
2041-6520
5957-5966
Leitch, Eilidh
1834bfc7-511a-4893-a022-1853731e6a16
Elumalai, Nagarajan
906d0161-3780-4778-ba5e-86ce313faf8d
Fridén-Saxin, Maria
f190492b-1f24-48a0-a89f-9514bd90039e
Dahl, Göran
bc7283b5-6aa9-4547-9e4e-7a6e99b33bfe
Wan, Paul
8ff658f3-78ca-4c74-b2b1-294701f20311
Clarkson, Paul
34a48390-e95c-4ea6-b71e-0183254decd4
Valeur, Eric
627bd8e1-da37-4b3a-864d-2e18fde8976d
Pairaudeau, Garry
d9ceac65-d200-4794-b7cd-fcf55dcfab68
Boyd, Helen
4421d365-f6b8-4048-b9ea-9f9700a9283e
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2
Leitch, Eilidh
1834bfc7-511a-4893-a022-1853731e6a16
Elumalai, Nagarajan
906d0161-3780-4778-ba5e-86ce313faf8d
Fridén-Saxin, Maria
f190492b-1f24-48a0-a89f-9514bd90039e
Dahl, Göran
bc7283b5-6aa9-4547-9e4e-7a6e99b33bfe
Wan, Paul
8ff658f3-78ca-4c74-b2b1-294701f20311
Clarkson, Paul
34a48390-e95c-4ea6-b71e-0183254decd4
Valeur, Eric
627bd8e1-da37-4b3a-864d-2e18fde8976d
Pairaudeau, Garry
d9ceac65-d200-4794-b7cd-fcf55dcfab68
Boyd, Helen
4421d365-f6b8-4048-b9ea-9f9700a9283e
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2

Leitch, Eilidh, Elumalai, Nagarajan, Fridén-Saxin, Maria, Dahl, Göran, Wan, Paul, Clarkson, Paul, Valeur, Eric, Pairaudeau, Garry, Boyd, Helen and Tavassoli, Ali (2018) Inhibition of low-density lipoprotein receptor degradation with a cyclic peptide that disrupts the homodimerization of IDOL E3 ubiquitin ligase. Chemical Science, 9 (27), 5957-5966. (doi:10.1039/c8sc01186a).

Record type: Article

Abstract

Cellular uptake of circulating cholesterol occurs via the low density lipoprotein receptor (LDLR). The E3 ubiquitin ligase IDOL is a mediator of LDLR degradation, with IDOL homodimerization thought to be required for its activity. To probe the possibility of modulating LDLR levels with an inhibitor of IDOL homodimerization, we screened a SICLOPPS library of 3.2 million cyclic peptides for compounds that disrupt this protein-protein interaction. We identified cyclo-CFFLYT as the lead inhibitor, and improved its activity through the incorporation of non-natural amino acids. The activity of the optimized cyclic peptide was assessed in hepatic cells, with a dose-dependent increase in LDLR levels observed in the presence of our IDOL homodimerization inhibitor.

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Accepted/In Press date: 17 June 2018
e-pub ahead of print date: 26 June 2018
Published date: 21 July 2018
Keywords: SICLOPPS, IDOL, cyclic peptide, LDLR, protein-protein interaction networks

Identifiers

Local EPrints ID: 421740
URI: http://eprints.soton.ac.uk/id/eprint/421740
ISSN: 2041-6520
PURE UUID: 716b36cc-7d45-4f80-b049-249a93f7964e
ORCID for Nagarajan Elumalai: ORCID iD orcid.org/0000-0001-7359-5218
ORCID for Ali Tavassoli: ORCID iD orcid.org/0000-0002-7420-5063

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Date deposited: 26 Jun 2018 16:30
Last modified: 18 Feb 2021 17:26

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Contributors

Author: Eilidh Leitch
Author: Maria Fridén-Saxin
Author: Göran Dahl
Author: Paul Wan
Author: Paul Clarkson
Author: Eric Valeur
Author: Garry Pairaudeau
Author: Helen Boyd
Author: Ali Tavassoli ORCID iD

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