Enhancing Cell Penetration Efficiency of Cyclic Oligoarginines Using Rigid Scaffolds

Bató, Csaba; Szabó, Ildikò; Bánóczi, Zoltán

doi:10.3390/pharmaceutics15061736

Cited by 3 publications

(4 citation statements)

References 47 publications

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“…Linear peptides were ordered from NovoPro Bioscience Inc. in the form of acetate salt and their purity were above 95%, tested by HPLC. The cyclic peptide was synthesized manually using Fmoc/tBu solid-phase peptide synthesis (SPPS) on Rink amide MBHA resin [56]. In the last step, the chloroacetyl group was introduced using pentachlorophenyl chloroacetate.…”

Section: Cyclization Of the Orf45 Peptidementioning

confidence: 99%

Phosphorylation-Assisted Luciferase Complementation Assay Designed to Monitor Kinase Activity and Kinase-Domain-Mediated Protein–Protein Binding

Póti,

Dénes,

Papp

et al. 2023

IJMS

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Protein kinases are key regulators of cell signaling and have been important therapeutic targets for three decades. ATP-competitive drugs directly inhibit the activity of kinases but these enzymes work as part of complex protein networks in which protein–protein interactions (often referred to as kinase docking) may govern a more complex activation pattern. Kinase docking is indispensable for many signaling disease-relevant Ser/Thr kinases and it is mediated by a dedicated surface groove on the kinase domain which is distinct from the substrate-binding pocket. Thus, interfering with kinase docking provides an alternative strategy to control kinases. We describe activity sensors developed for p90 ribosomal S6 kinase (RSK) and mitogen-activated protein kinases (MAPKs: ERK, p38, and JNK) whose substrate phosphorylation is known to depend on kinase-docking-groove-mediated protein–protein binding. The in vitro assays were based on fragment complementation of the NanoBit luciferase, which is facilitated upon substrate motif phosphorylation. The new phosphorylation-assisted luciferase complementation (PhALC) sensors are highly selective and the PhALC assay is a useful tool for the quantitative analysis of kinase activity or kinase docking, and even for high-throughput screening of academic compound collections.

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Section: Cyclization Of the Orf45 Peptidementioning

confidence: 99%

Phosphorylation-Assisted Luciferase Complementation Assay Designed to Monitor Kinase Activity and Kinase-Domain-Mediated Protein–Protein Binding

Póti,

Dénes,

Papp

et al. 2023

IJMS

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“…Among the numerous structural modifications for developing peptide mimics [ 14 , 15 ], the replacement of one or more amino acids by an aza-amino acid in which C α is replaced by nitrogen produces an aza-peptide ( Figure 1 ) [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…Among the numerous structural modifications for developing peptide mimics [14,15], the replacement of one or more amino acids by an aza-amino acid in which Cɑ is replaced by nitrogen produces an aza-peptide (Figure 1) [16]. The synthesis of building blocks of peptides containing aza-amino acid residues requires the use of hydrazine.…”

Section: Introductionmentioning

confidence: 99%

Influence of Aza-Glycine Substitution on the Internalization of Penetratin

Tarchoun,

Soltész,

Farkas

et al. 2024

Pharmaceutics

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The cell-penetrating peptide (CPP) penetratin has gained much attention over many years due to its potential role as a transporter for a broad range of cargo into cells. The modification of penetratin has been extensively investigated too. Aza-peptides are peptide analogs in which one or more of the amino residues are replaced by a semicarbazide. This substitution results in conformational restrictions and modifications in hydrogen bonding properties, which affect the structure and may lead to enhanced activity and selectivity of the modified peptide. In this work, the Trp residues of penetratin were substituted by aza-glycine or glycine residues to examine the effect of these modifications on the cellular uptake and the internalization mechanism. The substitution of Trp48 or Trp48,56 dramatically reduced the internalization, showing the importance of Trp48 in cellular uptake. Interestingly, while aza-glycine in the position of Trp56 increased the cellular uptake, Gly reduced it. The two Trp-modified derivatives showed altered internalization pathways, too. Based on our knowledge, this is the first study about the effect of aza-amino acid substitution on the cell entry of CPPs. Our results suggest that aza-amino acid insertion is a useful modification to change the internalization of a CPP.

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“…Cyclization is a standard method to increase the proteolytic resistance of pharmacologically active peptides, because the lack of free amino and carboxyl groups of N- and C -terminal amino acids makes cyclic peptides resistant towards blood exopeptidases ( Costa et al, 2023 ). The structures of the oligoarginine peptides can be stabilized by various modes of cyclization to improve their stability and cell-penetrating properties ( Bató et al, 2023 ). For example, on the basis of R8 its cyclic fluorescent analog has been prepared ( Fang et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of nicotinic acetylcholine receptors by oligoarginine peptides and polyamine-related compounds

Ojomoko,

Kryukova,

Egorova

et al. 2023

Front. Pharmacol.

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Oligoarginine peptides, known mostly for their cell-penetrating properties, are also inhibitors of the nicotinic acetylcholine receptors (nAChRs). Since octa-arginine (R8) inhibits α9α10 nAChR and suppresses neuropathic pain, we checked if other polycationic compounds containing amino and/or guanidino groups could be effective and tested the activity of the disulfide-fixed “cyclo”R8, a series of biogenic polyamines (putrescine, spermidine, and spermine), C-methylated spermine analogs, agmatine and its analogs, as well as acylpolyamine argiotoxin-636 from spider venom. Their inhibitory potency on muscle-type, α7 and α9α10 nAChRs was determined using radioligand analysis, electrophysiology, and calcium imaging. “Cyclo”R8 showed similar activity to that of R8 against α9α10 nAChR (IC50 ≈ 60 nM). Biogenic polyamines as well as agmatine and its analogs displayed low activity on muscle-type Torpedo californica, as well as α7 and α9α10 nAChRs, which increased with chain length, the most active being spermine and its C-methylated derivatives having IC50 of about 30 μM against muscle-type T. californica nAChR. Argiotoxin-636, which contains a polyamine backbone and terminal guanidino group, also weakly inhibited T. californica nAChR (IC50 ≈ 15 μM), but it revealed high potency against rat α9α10 nAChR (IC50 ≈ 200 nM). We conclude that oligoarginines and similar polycationic compounds effectively inhibiting α9α10 nAChR may serve as a basis for the development of analgesics to reduce neuropathic pain.

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Enhancing Cell Penetration Efficiency of Cyclic Oligoarginines Using Rigid Scaffolds

Cited by 3 publications

References 47 publications

Phosphorylation-Assisted Luciferase Complementation Assay Designed to Monitor Kinase Activity and Kinase-Domain-Mediated Protein–Protein Binding

Phosphorylation-Assisted Luciferase Complementation Assay Designed to Monitor Kinase Activity and Kinase-Domain-Mediated Protein–Protein Binding

Influence of Aza-Glycine Substitution on the Internalization of Penetratin

Inhibition of nicotinic acetylcholine receptors by oligoarginine peptides and polyamine-related compounds

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