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

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.

SUBMITTER: Leitch EK

PROVIDER: S-EPMC6050537 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Leitch Eilidh K EK Elumalai Nagarajan N Fridén-Saxin Maria M Dahl Göran G Wan Paul P Clarkson Paul P Valeur Eric E Pairaudeau Garry G Boyd Helen H Tavassoli Ali A

Chemical science 20180626 27

Cellular uptake of circulating cholesterol occurs <i>via</i> 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 <i>cyclo</i>-CFFLYT as the lea ...[more]

PMID: 30079210

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