Controlled inhibition of methyltransferases using photoswitchable peptidomimetics: towards an epigenetic regulation of leukemia. Issue 6 (5th May 2017)

• Record Type: Journal Article
• Authors: Albert, Lea; Xu, Jing; Wan, Ruiwei; Srinivasan, Vasundara; Dou, Yali; Vázquez, Olalla
• Is Part Of: Chemical science. Volume 8:Issue 6(2017)
• Page Start: 4612
• Page End: 4618
• Publication Date: 2017-05-05
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c7sc00137a
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : Shine light on epigenetics: we describe how photoswitchable peptidomimetics modulate the activity of the MLLl enzyme affecting epigenetic states. 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 ( K i = 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.