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Issue 27, 2018
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Inhibition of low-density lipoprotein receptor degradation with a cyclic peptide that disrupts the homodimerization of IDOL E3 ubiquitin ligase

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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.

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

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Publication details

The article was received on 13 Mar 2018, accepted on 14 Jun 2018 and first published on 26 Jun 2018


Article type: Edge Article
DOI: 10.1039/C8SC01186A
Citation: Chem. Sci., 2018,9, 5957-5966
  • Open access: Creative Commons BY license
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    Inhibition of low-density lipoprotein receptor degradation with a cyclic peptide that disrupts the homodimerization of IDOL E3 ubiquitin ligase

    E. K. Leitch, N. Elumalai, M. Fridén-Saxin, G. Dahl, P. Wan, P. Clarkson, E. Valeur, G. Pairaudeau, H. Boyd and A. Tavassoli, Chem. Sci., 2018, 9, 5957
    DOI: 10.1039/C8SC01186A

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