Title | Peptide-based inhibitors of Plk1 polo-box domain containing mono-anionic phosphothreonine esters and their pivaloyloxymethyl prodrugs. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Qian, W-J, Park, J-E, Lim, D, Park, S-Y, Lee, K-W, Yaffe, MB, Lee, KS, Burke, TR |
Journal | Chem Biol |
Volume | 20 |
Issue | 10 |
Pagination | 1255-64 |
Date Published | 2013 Oct 24 |
ISSN | 1879-1301 |
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 may be used to disrupt PBD function, 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. We report five-mer peptides containing mono-anionic pThr phosphoryl esters that exhibit single-digit nanomolar PBD binding affinities in extracellular assays and improved antimitotic efficacies in whole cell assays. The cellular efficacies of these peptides have been further enhanced by the application of bio-reversible pivaloyloxymethyl (POM) phosphoryl protection to a pThr-containing polypeptide. Our findings may redefine structural parameters for the development of PBD-binding peptides and peptide mimetics. |
DOI | 10.1016/j.chembiol.2013.09.005 |
Alternate Journal | Chem. Biol. |
PubMed ID | 24120332 |
PubMed Central ID | PMC3859306 |
Grant List | CA112967 / CA / NCI NIH HHS / United States GM104047 / GM / NIGMS NIH HHS / United States R01 ES015339 / ES / NIEHS NIH HHS / United States R01 GM104047 / GM / NIGMS NIH HHS / United States S015339 / / PHS HHS / United States U54 CA112967 / CA / NCI NIH HHS / United States |