Unknown

Dataset Information

0

Peptide-based inhibitors of Plk1 polo-box domain containing mono-anionic phosphothreonine esters and their pivaloyloxymethyl prodrugs.

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.

SUBMITTER: Qian WJ 

PROVIDER: S-EPMC3859306 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

Peptide-based inhibitors of Plk1 polo-box domain containing mono-anionic phosphothreonine esters and their pivaloyloxymethyl prodrugs.

Qian Wen-Jian WJ   Park Jung-Eun JE   Lim Dan D   Park Suk-Youl SY   Lee Ki-Won KW   Yaffe Michael B MB   Lee Kyung S KS   Burke Terrence R TR  

Chemistry & biology 20131010 10

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 contain  ...[more]

Similar Datasets

Unknown Mono-anionic phosphopeptides produced by unexpected histidine alkylation exhibit high Plk1 polo-box domain-binding affinities and enhanced antiproliferative effects in HeLa cells.
| S-EPMC4895914 | biostudies-literature
Unknown Phosphorylation- and polo-box-dependent binding of Plk1 to Bub1 is required for the kinetochore localization of Plk1.
| S-EPMC1525235 | biostudies-literature
Unknown Identification of high affinity polo-like kinase 1 (Plk1) polo-box domain binding peptides using oxime-based diversification.
| S-EPMC3355227 | biostudies-literature
Unknown Mechanisms underlying Plk1 polo-box domain-mediated biological processes and their physiological significance.
| S-EPMC4012076 | biostudies-literature
Unknown Peptoid-Peptide hybrid ligands targeting the polo box domain of polo-like kinase 1.
| S-EPMC4536914 | biostudies-literature
Unknown Proteomic screen defines the Polo-box domain interactome and identifies Rock2 as a Plk1 substrate.
| S-EPMC1864981 | biostudies-literature
Unknown Non-proteinogenic amino acids in the pThr-2 position of a pentamer peptide that confer high binding affinity for the polo box domain (PBD) of polo-like kinase 1 (Plk1).
| S-EPMC3530200 | biostudies-literature
Unknown A cryptic hydrophobic pocket in the polo-box domain of the polo-like kinase PLK1 regulates substrate recognition and mitotic chromosome segregation.
| S-EPMC6828814 | biostudies-literature
Unknown Targeting subcellular localization through the polo-box domain: non-ATP competitive inhibitors recapitulate a PLK1 phenotype.
| S-EPMC3711794 | biostudies-literature
Unknown Development of Highly Selective 1,2,3-Triazole-containing Peptidic Polo-like Kinase 1 Polo-box Domain-binding Inhibitors.
| S-EPMC6515314 | biostudies-literature