Promiscuous Ligands

McGovern, Susan L.

doi:10.1016/b0-08-045044-x/00053-5

Cited by 6 publications

(5 citation statements)

References 59 publications

(146 reference statements)

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“…Based on the above we selected peptides 2c and 2m for more in-depth evaluation. To rule out promiscuous modes of binding (Coan et al, 2009; McGovern, 2006), the Ser to Ala mutants (S4A) of 2c and 2m were prepared, since the Ser residue provides key recognition features for canonical Plk1 PBD binding and replacement with an Ala residue is known to significantly reduce binding affinity (Elia et al, 2003a). Consistent with non-promiscuous binding, our current study showed that the Ser to Ala substituted peptides exhibited approximately two orders-of-magnitude reduced inhibitory potencies [ 2c(S4A) IC 50 = 0.8 μM and 2m(S4A) IC 50 = 0.15 μM] (Table 1 and Figure S2).…”

Section: Resultsmentioning

confidence: 99%

RETRACTED: Peptide-Based Inhibitors of Plk1 Polo-box Domain Containing Mono-anionic Phosphothreonine Esters and Their Pivaloyloxymethyl Prodrugs

Qian¹,

Park²,

Lim³

et al. 2013

Chemistry & Biology

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SUMMARY 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. In our current paper 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 first 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.

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Section: Resultsmentioning

confidence: 99%

RETRACTED: Peptide-Based Inhibitors of Plk1 Polo-box Domain Containing Mono-anionic Phosphothreonine Esters and Their Pivaloyloxymethyl Prodrugs

Qian¹,

Park²,

Lim³

et al. 2013

Chemistry & Biology

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“…Because adding long chain n -alkylphenyl groups to 1 introduces significant hydrophobic character, we considered the possibility that “promiscuous” mechanisms unrelated to specific interactions with the PBD could give rise to apparent high binding affinity of the byproducts. 34 , 35 To address this question we made use of the fact that the “SpT” dipeptide motif is critical for specific high affinity Plk1 PBD-binding and that replacement of the serine residue by an alanine significantly reduces affinity. 20 Therefore, we prepared the corresponding analogues of 3j and 4j in which the serine residue was replaced with an alanine residue [ 3j(S4A) and 4j(S4A) , respectively] and we observed that this resulted in a significant loss of affinity ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

Serendipitous alkylation of a Plk1 ligand uncovers a new binding channel

et al. 2011

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In the current work, unanticipated synthetic byproducts were obtained arising from alkylation of the δ1 nitrogen (N3) of the histidine imidazole ring of the polo-like kinase-1 (Plk1) polo-box domain (PBD)-binding peptide PLHSpT. For the highest affinity byproduct, bearing a C6H5(CH2)8– group, a Plk1 PBD co-crystal structure revealed a new binding channel that had previously been occluded. An N-terminal PEGylated version of this peptide containing a hydrolytically-stable phosphothreonyl residue (pT) bound to the Plk1 PBD with affinity equal to the non-PEGylated parent, yet it exhibited significantly less interaction with the PBDs of the two closely-related Plk2 or Plk3. Treatment of cultured cells with this PEGylated peptide resulted in Plk1 delocalization from centrosomes and kinetochores, and chromosome misalignment that effectively induced mitotic block and apoptotic cell death. This work provides new insights that may advance efforts to develop Plk1 PBD-binding inhibitors as potential Plk1-specific anticancer therapeutic agents.

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“…Since n -alkylphenyl groups impart considerable hydrophobic character, we were concerned that these results may reflect ‘promiscuous’ binding mechanisms that do not rely on specific interactions with the PBD. [8] To examine this possibility, we made use of the fact that the ‘SpT’ dipeptide motif is crucial for specific high-affinity Plk1 PBD binding and that substitution of the serine residue by an alanine markedly reduces affinity. [9] We replaced the serine residue in 6q with an alanine residue [ 6q(S4A) ] and found that this resulted in a significant reduction in binding affinity (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

Peptoid–Peptide Hybrid Ligands Targeting the Polo Box Domain of Polo‐Like Kinase 1

Liu¹,

Park²,

Qian³

et al. 2012

ChemBioChem

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We replaced the amino terminal Pro residue of the Plk1 polo box domain-binding 5-mer peptide (PLHSpT) with a library of N-alkyl-Gly “peptoids” and identified long-chain tethered phenyl moieties giving greater than two-orders-of-magnitude affinity enhancement. Further simplification by replacing the peptoid residue with appropriate amides gave low-nanomolar affinity N-acylated tetrapeptides. Binding of the N-terminal long-chain phenyl extension was made clear by X-ray co-crystal data.

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Promiscuous Ligands

Cited by 6 publications

References 59 publications

RETRACTED: Peptide-Based Inhibitors of Plk1 Polo-box Domain Containing Mono-anionic Phosphothreonine Esters and Their Pivaloyloxymethyl Prodrugs

RETRACTED: Peptide-Based Inhibitors of Plk1 Polo-box Domain Containing Mono-anionic Phosphothreonine Esters and Their Pivaloyloxymethyl Prodrugs

Serendipitous alkylation of a Plk1 ligand uncovers a new binding channel

Peptoid–Peptide Hybrid Ligands Targeting the Polo Box Domain of Polo‐Like Kinase 1

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