Chemistry of Peptide Synthesis

Benoiton, N. Leo

doi:10.1201/9781420027693

Cited by 67 publications

(62 citation statements)

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“…LR (LSCQLYQR) and its [D-Gln 4 ] analog (LSCqLYQR) were obtained through canonical solid-phase peptide synthesis on Wang resin using Fmoc/t-Bu chemistry. 15 The crude peptides were further purified via standard preparative RP-HPLC, yielding a final product purity higher than 99%, as determined by HPLC-UV analysis. Membrane barrier crossing of the peptides was promoted by the SAINT PhD delivery system (Synvolux Therapeutics, NL), according to the standard transfection protocol; a 0.8 mM stock solution of the peptide was prepared in HBS and stored at −80°C before use.…”

Section: ■ Experimental Section Cell Culture and Treatmentmentioning

confidence: 99%

Mass Spectrometric/Bioinformatic Identification of a Protein Subset That Characterizes the Cellular Activity of Anticancer Peptides

et al. 2014

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The preclinical study of the mechanism of action of anticancer small molecules is challenging due to the complexity of cancer biology and the fragmentary nature of available data. With the aim of identifying a protein subset characterizing the cellular activity of anticancer peptides, we used differential mass spectrometry to identify proteomic changes induced by two peptides, LR and [d-Gln(4)]LR, that inhibit cell growth and compared them with the changes induced by a known drug, pemetrexed, targeting the same enzyme, thymidylate synthase. The quantification of the proteome of an ovarian cancer cell model treated with LR yielded a differentially expressed protein data set with respect to untreated cells. This core set was expanded by bioinformatic data interpretation, the biologically relevant proteins were selected, and their differential expression was validated on three cis-platinum sensitive and resistant ovarian cancer cell lines. Via clustering of the protein network features, a broader view of the peptides' cellular activity was obtained. Differences from the mechanism of action of pemetrexed were inferred from different modulation of the selected proteins. The protein subset identification represents a method of general applicability to characterize the cellular activity of preclinical compounds and a tool for monitoring the cellular activity of novel drug candidates.

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Section: ■ Experimental Section Cell Culture and Treatmentmentioning

confidence: 99%

Mass Spectrometric/Bioinformatic Identification of a Protein Subset That Characterizes the Cellular Activity of Anticancer Peptides

et al. 2014

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“…The peptide sequences LARLLT ( 1 ) and GYHWYGYTPQNVI ( 2 ) were synthesized on Fmoc-Pal-PEG-PS resin using solid phase peptide synthesis [10, 21]. An aminium coupling agent, TBTU, a triazole as electron-poor coupling additive, HOBt, and DIEA as base were used in the solid phase synthesis of 1 and 2 [10, 21–23]. A polar aprotic solvent, DMF, enabled the swelling of the Fmoc-PAL-PEG-PS resin, expanding the active sites and facilitated amino acid coupling to the resin.…”

Section: Resultsmentioning

confidence: 99%

Targeting of the epidermal growth factor receptor with mesoporphyrin IX-peptide conjugates

Fontenot

Ongarora

LeBlanc

et al. 2016

J. Porphyrins Phthalocyanines

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The synthesis and in vitro evaluation of four mesoporphyrin IX-peptide conjugates designed to target EGFR, over-expressed in colorectal and other cancers, are reported. Two peptides with known affinity for EGFR, LARLLT (1) and GYHWYGYTPQNVI (2), were conjugated to mesoporphyrin IX (MPIX, 3) via one or both the propionic side chains, directly (4, 5) or with a triethylene glycol spacer (7, 8). The conjugates were characterized using NMR, MS, CD, SPR, UV-vis and fluorescence spectroscopies. Energy minimization and molecular dynamics suggest different conformations for the conjugates. SPR studies show that conjugate 4, bearing two LARLLT with no PEG spacers, has the greatest affinity for binding to EGFR, followed by conjugate 7 with two PEG and two LARLLT sequences. Molecular modeling and docking studies suggest that both conjugates 4 and 7 can bind to monomer and dimer EGFR in open and closed conformations. The cytotoxicity and cellular targeting ability of the conjugates were investigated in human HEp2 cells over-expressing EGFR. All conjugates showed low dark- and photo-toxicities. The cellular uptake was highest for conjugates 4 and 8 and lowest for 7 bearing two LARLLT linked via PEG groups, likely due to decreased hydrophobicity. Among the conjugates investigated 4 is the most efficient EGFR-targeting agent, and therefore the most promising for the detection of cancers that over-express EGFR.

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“…Firstly, [Dmt 1 Cys 14 ]N/OFQ(1-14)-NH 2 was synthesised by solid phase method with an automatic solid phase peptide synthesizer Syro II (Biotage, Uppsala Sweden) using Fmoc/tBu chemistry (Benotoin NL., 2005). The resin 4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucyl-MBHA (Rink amide MBHA resin) was used as a solid support.…”

Section: Methodsmentioning

confidence: 99%

Pharmacological studies on the NOP and opioid receptor agonist PWT2-[Dmt1]N/OFQ(1-13)

Cerlesi

Ding

Bird

et al. 2017

European Journal of Pharmacology

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An innovative chemical strategy named peptide welding technology (PWT) has been developed for the facile synthesis of tetrabranched peptides. [Dmt1]N/OFQ(1-13)-NH2 acts as a universal agonist for nociceptin/orphanin FQ (N/OFQ) and classical opioid receptors. The present study investigated the pharmacological profile of the PWT derivative of [Dmt1]N/OFQ(1-13)NH2 (PWT2-[Dmt1]) in several assays in vitro and in vivo after spinal administration in monkeys subjected to the tail withdrawal assay. PWT2-[Dmt1] mimicked the effects of [Dmt1]N/OFQ(1-13)-NH2 displaying full agonist activity, similar affinity/potency and selectivity at human recombinant N/OFQ (NOP) and opioid receptors in receptor binding, stimulation of [35S]GTPγS binding, calcium mobilization in cells expressing chimeric G proteins, and BRET studies for measuring receptor/G-protein and receptor/β-arrestin 2 interaction. In vivo in monkeys PWT2-[Dmt1] elicited dose-dependent and robust antinociceptive effects being more potent and longer lasting than [Dmt1]N/OFQ(1-13)-NH2. The analgesic action of PWT2-[Dmt1] was sensitive to the NOP receptor antagonist J-113397, but not naltrexone. Thus, the present study demonstrated that the tetrabranched derivative of [Dmt1]N/OFQ(1-13)-NH2 obtained with the PWT technology maintains the in vitro pharmacological profile of the parent peptide but displays higher potency and longer lasting action in vivo.

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Chemistry of Peptide Synthesis

Cited by 67 publications

References 0 publications

Mass Spectrometric/Bioinformatic Identification of a Protein Subset That Characterizes the Cellular Activity of Anticancer Peptides

Mass Spectrometric/Bioinformatic Identification of a Protein Subset That Characterizes the Cellular Activity of Anticancer Peptides

Targeting of the epidermal growth factor receptor with mesoporphyrin IX-peptide conjugates

Pharmacological studies on the NOP and opioid receptor agonist PWT2-[Dmt1]N/OFQ(1-13)

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