Bifunctional Ligands for Inhibition of Tight-Binding Protein–Protein Interactions

Ivan, Taavi; Enkvist, Erki; Viira, Birgit; Manoharan, Ganesh babu; Raidaru, Gerda; Pflug, A.; Alam, Kazi Asraful; Zaccolo, Manuela; Engh, Richard A.; Uri, Asko

doi:10.1021/acs.bioconjchem.6b00293

Cited by 20 publications

(40 citation statements)

References 68 publications

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“…First, it is less hydrophobic than some other potent ATP-competitive compounds,s uch as 4,5,6,7-tetrabromobenzimidazole. [25] In the present study,s eries of conjugateso fA TB and ap eptide analogue were constructedw ith the aim fora pplication in cellular studies (Table 1). [24] Third, the moiety possesses good photoluminescence (fluorescence) properties, which enables its sensitive quantification with HPLC ( Figure S1).…”

Section: Resultsmentioning

confidence: 99%

“…This is especially criticali fanovel structural scaffold is introduced into the design. [25] In the present study,s eries of conjugateso fA TB and ap eptide analogue were constructedw ith the aim fora pplication in cellular studies (Table 1). First, the oligo-aspartate moiety present in previously reported compounds [18,19] was replaced with the corresponding carboxylate-rich peptoid chain comprising N-carboxymethylglycine (iminodiacetic acid, Ida) residues.…”

Section: Construction Of High-affinity Ck2 Inhibitorsmentioning

confidence: 99%

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A Selective Biligand Inhibitor of CK2 Increases Caspase‐3 Activity in Cancer Cells and Inhibits Platelet Aggregation

et al. 2017

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Cancer cells express high levels of CK2, and its inhibition leads to apoptosis. CK2 has therefore emerged as a new drug target for cancer therapy. A biligand inhibitor ARC-772 was constructed by conjugating 4-(2-amino-1,3-thiazol-5-yl)benzoic acid and a carboxylate-rich peptoid. ARC-772 was found to bind CK2 with a K value of 0.3 nm and showed remarkable CK2 inhibitory selectivity in a panel of 140 protein kinases (Gini coefficient: 0.75 at c=100 nm). ARC-775, the acetoxymethyl ester prodrug of ARC-772, was efficiently taken up by cells. Once internalized, the inhibitor is activated by cellular esterase activity. In HeLa cancer cells ARC-775 was found to activate caspase-3 (an apoptosis marker) at sub-micromolar concentrations (EC =0.3 μm), a 20-fold lower extracellular concentration than CX-4945, the only CK2 inhibitor under clinical trials. At micromolar concentrations, ARC-775 was also found to inhibit ADP-induced aggregation of human platelets. The overall results of this study demonstrate that oligo-anionic biligand inhibitors have good potential for drug development.

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Section: Resultsmentioning

confidence: 99%

Section: Construction Of High-affinity Ck2 Inhibitorsmentioning

confidence: 99%

A Selective Biligand Inhibitor of CK2 Increases Caspase‐3 Activity in Cancer Cells and Inhibits Platelet Aggregation

et al. 2017

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“…An alternative strategy has been employed by generating bi-substrate inhibitors of PKA where an ATP-competitive small molecule is conjugated to a peptidic moiety [22]. While some adenosine-oligoarginine conjugates (ARCs) were found to have high potency with K D values as low as 3 pM and IC 50 values in the low nanomolar range due to avidity effects [23], ease of synthesis of these compounds and cell permeation remains a challenge.…”

Section: Resultsmentioning

confidence: 99%

A Stapled Peptide Mimic of the Pseudosubstrate Inhibitor PKI Inhibits Protein Kinase A

et al. 2019

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Kinases regulate multiple and diverse signaling pathways and misregulation is implicated in a multitude of diseases. Although significant efforts have been put forth to develop kinase-specific inhibitors, specificity remains a challenge. As an alternative to catalytic inhibition, allosteric inhibitors can target areas on the surface of an enzyme, thereby providing additional target diversity. Using cAMP-dependent protein kinase A (PKA) as a model system, we sought to develop a hydrocarbon-stapled peptide targeting the pseudosubstrate domain of the kinase. A library of peptides was designed from a Protein Kinase Inhibitor (PKI), a naturally encoded protein that serves as a pseudosubstrate inhibitor for PKA. The binding properties of these peptide analogs were characterized by fluorescence polarization and surface plasmon resonance, and two compounds were identified with KD values in the 500–600 pM range. In kinase activity assays, both compounds demonstrated inhibition with 25–35 nM IC50 values. They were also found to permeate cells and localize within the cytoplasm and inhibited PKA activity within the cellular environment. To the best of our knowledge, these stapled peptide inhibitors represent some of the highest affinity binders reported to date for hydrocarbon stapled peptides.

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“…Fortunately, it has been demonstrated that some small molecules are capable to inhibit this interaction. For instance, bifunctional ligand for inhibiting tight-binding protein-protein interactions (Ivan et al 2016). Within this angle falls 1-Oleoyl-R-glycerol ligand or called (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate (Kim et al 2019).…”

Section: Introductionmentioning

confidence: 99%

In Silico Studies on Structural Function of Melanin Concentrating Hormone Receptor 1 Through Docking Approach, Towards Designing Drug for Treating Obesity

Mutangana¹,

Narcisse²,

Gaetan³

et al. 2020

RJESTE

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Melanin concentrating hormone receptor 1 is a G-protein coupled protein receptor expressed in the lateral hypothalamus and zona incerta, part of the nervous system that regulates feeding behavior and energy homeostasis. It is involved in the stimulation of appetite, this was seen when synthetic MCHR1 or MCH was administered to mice and it resulted in induced obesity due to the enhanced feeding. Many researchers have successfully find out the functions of several proteins, using computational approach. It is in this context that in this study the structural function of melanin concentrating hormone receptor 1 through docking studies has been done to make sure that those who are working to address the problem of obesity while trying to discover the effective drugs gain much insight about this receptor. The in silico methods have been used to predict the model of melanin concentrating hormone receptor 1. The template used for model prediction was human delta opioid receptor with the accession number 4N6H. The predicted model has been evaluated and found to be of good quality. Docking was done to investigate the interaction between the ligand; a bifunctional peptide ‘1-oleoyl-r-glycerol’ and the predicted model of melanin concentrating hormone receptor 1 which showed that fourteen residues interacted between the predicted model and ligand. Among interacting residues, it was realized that some of them are involved in sugar metabolism. Thus this study suggests a potential candidate for drug design against cancer and diabetes. Keywords: obesity, MCHR-1, docking, structural function, 3D structure, phylogenetic analysis, interacting residues

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Bifunctional Ligands for Inhibition of Tight-Binding Protein–Protein Interactions

Cited by 20 publications

References 68 publications

A Selective Biligand Inhibitor of CK2 Increases Caspase‐3 Activity in Cancer Cells and Inhibits Platelet Aggregation

A Selective Biligand Inhibitor of CK2 Increases Caspase‐3 Activity in Cancer Cells and Inhibits Platelet Aggregation

A Stapled Peptide Mimic of the Pseudosubstrate Inhibitor PKI Inhibits Protein Kinase A

In Silico Studies on Structural Function of Melanin Concentrating Hormone Receptor 1 Through Docking Approach, Towards Designing Drug for Treating Obesity

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