A Combinatorial Peptoid Library for the Identification of Novel MSH and GRP / Bombesin Receptor Ligands

Heizmann, Gerhard; Hildebrand, Pius; Tanner, Heidi; Ketterer, Sylvia; Pansky, Andreas; Froidevaux, Sylvie; Beglinger, Christoph; Eberlé, Alex N.

doi:10.3109/10799899909036664

Cited by 36 publications

(34 citation statements)

References 18 publications

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“…This can be achieved by placing the original amino acid side‐chain on the amide nitrogen instead of on the α‐carbon atom. In essence, this represents substitution of the original amino acid residue by an N ‐substituted glycine analog, a so‐called peptoid residue 1–16. The corresponding oligomeric compounds are called peptoids.…”

Section: Introductionmentioning

confidence: 99%

Characterization of a phosphorylated peptide and peptoid and peptoid–peptide hybrids by mass spectrometry

Ruijtenbeek

Versluis²,

Heck³

et al. 2001

J. Mass Spectrom.

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Nano-electrospray tandem mass spectrometry (nano-ES-MS/MS) was used to record collision-induced dissociation (CID) spectra of a set of peptoid-peptide hybrids and the complete peptoid derived from the phosphopeptide Ac-pTyr-Glu-Thr-Leu-NH(2) (1). The presence of B and Y''-type fragment ions in the tandem mass spectra of the protonated molecular ions [M + H](+) allowed confirmation of sequence similar to mass spectrometric sequence analysis in peptides. In the isomeric peptoid compounds studied, one or several amino acid residues were replaced by peptoid residues (N-substituted glycine residues), which resulted in characteristic tandem mass spectra with differently increased relative abundances of Y''-and B-type fragment ions. The increment of a particular Y''-ion was directly correlated to the position of a peptoid residue present. In addition to these increased peak intensities, other characteristic peaks were also observed compared with the spectrum of reference peptide 1. When a peptoid phosphotyrosine was incorporated, the presence of this residue was apparent from the occurrence of a relatively intense peak at m/z 187 representing the positively charged side-chain of phosphotyrosine, which was almost absent in the spectrum of the reference peptide 1. Since the threonine side-chain had to be translated into the homo peptoid analog this substitution was apparent from the presence of [M + H](+) and fragment ions 14 mass units higher than observed in the spectrum of the reference phosphopeptide 1. The presence of an NLeu peptoid residue could be confirmed by the specific fragmentation of the immonium ion showing an intense peak in its tandem mass spectrum at m/z 57, which results from the loss of an neutral imine molecule leading to a positively charged [C(4)H(9)](+) ion. By means of these mass spectrometric characteristics, all isomeric peptoid compounds could be distinguished from each other and characterized. The methods used appear to be very useful in future studies of peptoids and peptoid-peptide hybrids.

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Section: Introductionmentioning

confidence: 99%

Characterization of a phosphorylated peptide and peptoid and peptoid–peptide hybrids by mass spectrometry

Ruijtenbeek

Versluis²,

Heck³

et al. 2001

J. Mass Spectrom.

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“…Trimers of N-alkylglycines are a family of non-natural molecules that are attractive for the drug discovery process because of their broad variety of biological activities. They have been successfully used for the identification of diverse activity, ranging from high-affinity ligands for membrane receptors to disruptors of macromolecular complexes (Heizmann et al, 1999;Humet et al, 2003). Furthermore, N-trialkylglycines have been used to identify anti-inflammatory, analgesic, and neuroprotectant drugs that exhibit in vivo activity Montoliu et al, 2002;Planells-Cases et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Trimers ofN-Alkylglycines Are Potent Modulators of the Multidrug Resistance Phenotype

Abad-Merin

Cortés²,

Masip³

et al. 2005

J Pharmacol Exp Ther

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The multidrug resistance (MDR) phenotype is considered a major cause of the failure of cancer chemotherapy. The acquisition of MDR is usually mediated by the overexpression of drug efflux pumps such as glycoprotein P (P-gp) or multidrug resistancerelated protein 1 (MRP1). Thus, the identification, validation, and development of compounds that mitigate the MDR phenotype by modulating the activity of these transport proteins is an important yet elusive target. Here, we have addressed this issue and screened an N-trialkylglycine-based combinatorial library composed of 5120 compounds to search for modulators of the MDR phenotype. The screening identified 20 trimers of N-alkylglycine that increased the intracellular accumulation of daunomycin (DNM) in drug-resistant L1210R tumor cells that overexpressed the P-gp. These compounds seem to act as P-gp antagonists, as evidenced by the augmentation of DNM accumulation in the L1210 P-gp cell line, a drug-sensitive L1210 cell stably expressing the murine P-gp protein. Similarly, several of the active N-trialkylglycines also produced an increment in DNM uptake in human HL60R cells, which primarily express the MRP1 protein. Trialkylglycines notably sensitized L1210R and HL60R tumor cells to DNM with a potency that rivaled that of verapamil. These findings provide new molecular scaffolds for the development of effective chemosensitizers against the MDR phenotype that, in due turn, could be used as adjuvant drugs in cancer chemotherapy.

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“…Heizmann et al [50] tested a peptoid library containing 328,509 compounds and successfully identified new ligands for both α-MSH receptor and GRP-preferring bombesin receptor. The K D values calculated from competition binding data were 1.58 μM ( 4 ) and 3.4 μM ( 5 ), respectively.…”

Section: Gpcr Ligands From Oboc Combinatorial Librariesmentioning

confidence: 99%

The Identification of High-Affinity G Protein-Coupled Receptor Ligands from Large Combinatorial Libraries Using Multicolor Quantum Dot-Labeled Cell-Based Screening

Lee

2014

Future Med. Chem.

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G protein-coupled receptors (GPCRs), which are involved in virtually every biological process, constitute the largest family of transmembrane receptors. Many top-selling and newly approved drugs target GPCRs. In this review, we aim to recapitulate efforts and progress in combinatorial library-assisted GPCR ligand discovery, particularly focusing on one-bead-one-compound library synthesis and quantum dot-labeled cell-based assays, which both effectively enhance the rapid identification of GPCR ligands with higher affinity and specificity.

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A Combinatorial Peptoid Library for the Identification of Novel MSH and GRP / Bombesin Receptor Ligands

Cited by 36 publications

References 18 publications

Characterization of a phosphorylated peptide and peptoid and peptoid–peptide hybrids by mass spectrometry

Characterization of a phosphorylated peptide and peptoid and peptoid–peptide hybrids by mass spectrometry

Trimers ofN-Alkylglycines Are Potent Modulators of the Multidrug Resistance Phenotype

The Identification of High-Affinity G Protein-Coupled Receptor Ligands from Large Combinatorial Libraries Using Multicolor Quantum Dot-Labeled Cell-Based Screening

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