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Issue 6, 2017
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Controlled inhibition of methyltransferases using photoswitchable peptidomimetics: towards an epigenetic regulation of leukemia

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Abstract

We describe a cell-permeable photoswitchable probe capable of modulating epigenetic cellular states by disruption of an essential protein–protein interaction within the MLL1 methyltransferase core complex. Our azobenzene-containing peptides selectively block the WDR5-MLL1 interaction by binding to WDR5 with high affinity (Ki = 1.25 nM). We determined the co-crystal structure of this photoswitchable peptiomimetic with WDR5 to understand the interaction at the atomic level. Importantly, the photoswitchable trans and cis conformers of the probe display a clear difference in their inhibition of MLL1. We further demonstrate that the designed photo-controllable azo-peptidomimetics affect the transcription of the MLL1-target gene Deptor, which regulates hematopoiesis and leukemogenesis, and inhibit the growth of leukemia cells. This strategy demonstrates the potential of photopharmacological inhibition of methyltransferase protein–protein interactions as a novel method for external epigenetic control, providing a new toolbox for controlling epigenetic states.

Graphical abstract: Controlled inhibition of methyltransferases using photoswitchable peptidomimetics: towards an epigenetic regulation of leukemia

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Publication details

The article was received on 11 Jan 2017, accepted on 09 Apr 2017 and first published on 27 Apr 2017


Article type: Edge Article
DOI: 10.1039/C7SC00137A
Citation: Chem. Sci., 2017,8, 4612-4618
  • Open access: Creative Commons BY license
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    Controlled inhibition of methyltransferases using photoswitchable peptidomimetics: towards an epigenetic regulation of leukemia

    L. Albert, J. Xu, R. Wan, V. Srinivasan, Y. Dou and O. Vázquez, Chem. Sci., 2017, 8, 4612
    DOI: 10.1039/C7SC00137A

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