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

Liu, Fa; Park, Jung‐Eun; Qian, Wen‐Jian; Lim, Desmond R.; Scharow, Andrej; Berg, Thorsten; Yaffe, Michael B.; Lee, Kyung S.; Burke, Terrence R.

doi:10.1002/cbic.201200206

Cited by 39 publications

(41 citation statements)

References 30 publications

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“…Starting from the polo-box interacting protein 1 (PBIP) pT78-derived peptide PLHSpT ( 1 ), 11 we have previously reported that appending alkylphenyl groups from different positions on the peptide, including the His N(π)-position [the sequence having a (CH 2 ) 8 Ph group appended is designated as PLH*SpT ( 2a )], 12 the 4-position on the Pro residue ( 3 ) 13 and an amino-terminal N -alkyl Gly residue ( 4 ), 14 can result in up to one thousand-fold enhancement in Plk1 PBD-binding affinity (Figure 1). We found in each case that the alkylphenyl groups bind within a “cryptic binding pocket” on the PBD surface, which is defined by PBD residues Y417, Y421, Y481, L478, F482 and Y485 and revealed by rotation of the Y481 side chain (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Enhancing polo-like kinase 1 selectivity of polo-box domain-binding peptides

Zhao

Hymel

Burke

2017

Bioorganic & Medicinal Chemistry

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Section: Introductionmentioning

confidence: 99%

Enhancing polo-like kinase 1 selectivity of polo-box domain-binding peptides

Zhao

Hymel

Burke

2017

Bioorganic & Medicinal Chemistry

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“…Since then, the Tyr-rich hydrophobic channel has been targeted to develop the potent Plk1 PBD peptide inhibitors [14−18]. But, the above channel is conserved among the three Plks (Plk1–3) [11], and as a result, a loss of Plk1 PBD monospecificity was observed [12,14,15]. In contrast to the deep understanding of the Tyr-rich hydrophobic channel, the binding nature of the pyrrolidine-binding pocket was not explored much on a molecular basis, even though there has been a high possibility of achieving monospecificity at this binding site.…”

Section: Introductionmentioning

confidence: 99%

Exploring the Binding Nature of Pyrrolidine Pocket-Dependent Interactions in the Polo-Box Domain of Polo-Like Kinase 1

et al. 2013

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BackgroundOver the years, a great deal of effort has been focused on the design and synthesis of potent, linear peptide inhibitors targeting the polo-like kinase 1 (Plk1), which is critically involved in multiple mitotic processes and has been established as an adverse prognostic marker for tumor patients. Plk1 localizes to its intracellular anchoring sites via its polo-box domain, and inhibiting the Plk1 polo-box domain has been considered as an approach to circumvent the specificity problems associated with inhibiting the conserved adenosine triphosphate-binding pocket. The polo-box domain consists of two different binding regions, such as the unique, broader pyrrolidine-binding pocket and the conserved, narrow, Tyr-rich hydrophobic channel, among the three Plk polo-box domains (Plks 1–3), respectively. Therefore, the studies that provide insights into the binding nature of the unique, broader pyrrolidine-binding pocket might lead to the development of selective Plk1-inhibitory compounds.Methodology/Principal FindingsIn an attempt to retain the monospecificity by targeting the unique, broader pyrrolidine-binding pocket, here, for the first time, a systematic approach was undertaken to examine the structure-activity relationship of N-terminal-truncated PLHSpTM derivatives, to apply a site-directed ligand approach using bulky aromatic and non-aromatic systems, and to characterize the binding nature of these analogues using X-ray crystallographic studies. We have identified a new mode of binding interactions, having improved binding affinity and retaining the Plk1 polo-box domain specificity, at the pyrrolidine-binding pocket. Furthermore, our data revealed that the pyrrolidine-binding pocket was very specific to recognize a short and bulky hydrophobic ligand like adamantane, whereas the Tyr-rich hydrophobic channel was specific with lengthy and small hydrophobic groups.Conclusion/SignificanceThe progress made using our site-directed ligands validated this approach to specifically direct the ligand into the unique pyrrolidine-binding region, and it extends the applicability of the strategy for discovering selective protein-protein interaction inhibitors.

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“…7 Independently, we have found by tethering alkylphenyl groups from different positions on the shorter sequence PLHSpT ( 1 ), that we can occupy the cryptic binding pocket and achieve up to three-orders-of-magnitude enhancement in PBD-binding affinity. 8-10 Of particular note, we were able to reach the pocket from the His residue using peptides of the form PLH*SpT ( 2 ), where H* indicates the presence of a -(CH 2 ) 8 Ph group on the His N3 (π) nitrogen [ie, the His-[ N(π) -(CH 2 ) 8 Ph] (Figure 1). 8,11 This is significant for developing reduced-size binding antagonists, since this residue is at the pT-2 position, which is immediately adjacent to the “SpT” minimal recognition motif.…”

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Application of oxime-diversification to optimize ligand interactions within a cryptic pocket of the polo-like kinase 1 polo-box domain

Zhao

Hymel

Burke

2016

Bioorganic & Medicinal Chemistry Letters

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By a process involving initial screening of a set of 87 aldehydes using an oxime ligation-based strategy, we were able to achieve a several-fold affinity enhancement over one of the most potent previously known polo-like kinase 1 (Plk1) polo-box domain (PBD) binding inhibitors. This improved binding may result by accessing a newly identified auxiliary region proximal to a key hydrophobic cryptic pocket on the surface of the protein. Our findings could have general applicability to the design of PBD-binding antagonists.

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

Cited by 39 publications

References 30 publications

Enhancing polo-like kinase 1 selectivity of polo-box domain-binding peptides

Enhancing polo-like kinase 1 selectivity of polo-box domain-binding peptides

Exploring the Binding Nature of Pyrrolidine Pocket-Dependent Interactions in the Polo-Box Domain of Polo-Like Kinase 1

Application of oxime-diversification to optimize ligand interactions within a cryptic pocket of the polo-like kinase 1 polo-box domain

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