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Controlled inhibition of methyltransferases using photoswitchable peptidomimetics

June 21, 2017

We find here a new strategy for external epigenetic control, through targeting protein–protein interactions within a multi-protein complex, with peptidomimetic photoswitches.

Chemical Science; 2017, 8 (6), 4612-4618.
Controlled inhibition of methyltransferases using photoswitchable peptidomimetics: towards an epigenetic regulation of leukemia


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.

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