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Mono‐anionic phosphopeptides produced by unexpected histidine alkylation exhibit high plk1 polo‐box domain‐binding affinities and enhanced antiproliferative effects in hela cells
Author(s) -
Qian WenJian,
Park JungEun,
Lim Dan,
Lai Christopher C.,
Kelley James A.,
Park SukYoul,
Lee Ki Won,
Yaffe Michael B.,
Lee Kyung S.,
Burke Terrence R.
Publication year - 2014
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.22569
Subject(s) - chemistry , phosphoserine , plk1 , affinities , peptide , histidine , stereochemistry , biochemistry , hela , kinase , serine , phosphorylation , cell , amino acid , cell cycle
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. © 2014 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 444–455, 2014.