Mono-anionic phosphopeptides produced by unexpected histidine alkylation exhibit high plk1 polo-box domain-binding affinities and enhanced antiproliferative effects in hela cells
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Author(s)
Qian, Wen-Jian
Park, Jung-Eun
Lai, Christopher C.
Kelley, James A.
Park, Suk-Youl
Lee, Ki Won
Lee, Kyung S.
Burke, Terrence R.
Lim, Daniel Cham-Chin
Yaffe, Michael B
Date Issued
November 2014
Journal
Biopolymers
Publisher
Wiley Blackwell
Citation
Qian, Wen-Jian et al. “Mono-Anionic Phosphopeptides Produced by Unexpected Histidine Alkylation Exhibit High plk1 Polo-Box Domain-Binding Affinities and Enhanced Antiproliferative Effects in Hela Cells: Antiproliferative Effects in HeLa Cells.” Biopolymers 102.6 (2014): 444–455.
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Author's final manuscript
Abstract
Binding of polo-like kinase 1 (Plk1) polo-box domains (PBDs) to phosphothreonine (pThr)/phosphoserine (pSer)-containing sequences is critical for the proper function of Plk1. Although high-affinity synthetic pThr-containing peptides provide starting points for developing PBD-directed inhibitors, to date the efficacy of such peptides in whole cell assays has been poor. This potentially reflects limited cell membrane permeability arising, in part, from the di-anionic nature of the phosphoryl group or its mimetics. In our current article we report the unanticipated on-resin N(τ)-alkylation of histidine residues already bearing a N(π)- alkyl group. This resulted in cationic imidazolium-containing pThr peptides, several of which exhibit single-digit nanomolar PBD-binding affinities in extracellular assays and improved antimitotic efficacies in intact cells. We enhanced the cellular efficacies of these peptides further by applying bio-reversible pivaloyloxymethyl (POM) phosphoryl protection. New structural insights presented in our current study, including the potential utility of intramolecular charge masking, may be useful for the further development of PBD-binding peptides and peptide mimetics.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1002/bip.22569
