Automated Mass Spectrometric Sequence Determination of Cyclic Peptide Library Members

Redman, James E.; Wilcoxen, Keith; Ghadiri, Mojtaba

doi:10.1021/cc0200639

Cited by 59 publications

(51 citation statements)

References 46 publications

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“…The plates were centrifuged, the supernatant was removed, and the volatiles were evaporated. The residue was dissolved in 5% DMSO in water to prepare nominal 200-g/ml stock solutions (concentration estimate based on average theoretical yields and resin loading) for biological assays and mass spectrometry sequence determination (28). The final yield per bead was approximately 100 g.…”

Section: Methodsmentioning

confidence: 99%

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Systemic Antibacterial Activity of Novel Synthetic Cyclic Peptides

Dartois

Sánchez‐Quesada

Cabezas

et al. 2005

Antimicrob Agents Chemother

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147

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Cyclic peptides with an even number of alternating D,L-␣-amino acid residues are known to self-assemble into organic nanotubes. Such peptides previously have been shown to be stable upon protease treatment, membrane active, and bactericidal and to exert antimicrobial activity against Staphylococcus aureus and other gram-positive bacteria. The present report describes the in vitro and in vivo pharmacology of selected members of this cyclic peptide family. The intravenous (i.v.) efficacy of six compounds with MICs of less than 12 g/ml was tested in peritonitis and neutropenic-mouse thigh infection models. Four of the six peptides were efficacious in vivo, with 50% effective doses in the peritonitis model ranging between 4.0 and 6.7 mg/kg against methicillin-sensitive S. aureus (MSSA). In the thigh infection model, the four peptides reduced the bacterial load 2.1 to 3.0 log units following administration of an 8-mg/kg i.v. dose. Activity against methicillin-resistant S. aureus was similar to MSSA. The murine pharmacokinetic profile of each compound was determined following i.v. bolus injection. Interestingly, those compounds with poor efficacy in vivo displayed a significantly lower maximum concentration of the drug in serum and a higher volume of distribution at steady state than compounds with good therapeutic properties. S. aureus was unable to easily develop spontaneous resistance upon prolonged exposure to the peptides at sublethal concentrations, in agreement with the proposed interaction with multiple components of the bacterial membrane canopy. Although additional structure-activity relationship studies are required to improve the therapeutic window of this class of antimicrobial peptides, our results suggest that these amphipathic cyclic D,L-␣-peptides have potential for systemic administration and treatment of otherwise antibiotic-resistant infections.The incidence of community-acquired and nosocomially acquired infections due to the bacterium Staphylococcus aureus is rising (25). From 1990 to 1992, this microorganism was the most common cause of nosocomial pneumonias and surgical wound infections (14). The overall growing crisis in antibiotic resistance and the rise in the incidence of methicillin-resistant S. aureus (MRSA) strains (32, 33) have emphasized the need for therapeutic alternatives to currently available antibiotics. Vancomycin remains the mainstay of therapy against several resistant gram-positive pathogens. However, vancomycin is slowly bactericidal, and with the recent increase in nosocomial infections caused by vancomycin-resistant enterococci and S. aureus (4, 13, 16), there is a growing need for antimicrobial agents with novel mechanisms of action to attack these resistant pathogens. The Food and Drug Administration recently approved the use of daptomycin, a cyclic lipodepsipeptide antibiotic, for the treatment of complicated skin and skin structure infections caused by several gram-positive bacteria. Its mode of action seems to be related to the disruption of the membrane potential of ...

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Section: Methodsmentioning

confidence: 99%

“…Mass spectrometry was used as previously reported (28) to determine the likely sequence of cyclic peptide library members. Fidelity for the identification routinely was Ͼ90%.…”

Section: Methodsmentioning

confidence: 99%

Systemic Antibacterial Activity of Novel Synthetic Cyclic Peptides

Dartois

Sánchez‐Quesada

Cabezas

et al. 2005

Antimicrob Agents Chemother

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147

122

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“…The direct analysis of resin-bound peptides by Edman degradation is expensive and time consuming, making it impractical for the routine sequencing of large numbers of peptides (>100) [4]. Furthermore, this technique is not generally applicable as it requires free N-terminal amino group and is limited by the peptide chain length [5]. However, the fundamental problem of OBOC peptide library analysis is the small amount of compound obtained from a single resin bead and insufficient ionization efficiency of some peptides for standard ESI-MS analysis.…”

Section: Introductionmentioning

confidence: 99%

Sensitive electrospray mass spectrometry analysis of one-bead-one-compound peptide libraries labeled by quaternary ammonium salts

et al. 2012

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A rapid and straightforward method for highthroughput analysis of single resin beads from one-beadone-compound combinatorial libraries with high resolution electrospray ionization tandem mass spectrometry (HR ESI-MS/MS) is presented. The application of an efficient method of peptide derivatization by quaternary ammonium salts (QAS) formation increases ionization efficiency and reduces the detection limit, allowing analysis of trace amounts of compounds by ESI-MS. Peptides, synthesized on solid support, contain a new cleavable linker composed of a Peg spacer (9-aza-3,6,12,15-tetraoxa-10-on-heptadecanoic acid), lysine with ε-amino group marked by the N,N,N-triethylglycine salt, and methionine, which makes possible the selective cleavage by cyanogen bromide. Even a small portion of peptides derivatized by QAS cleaved from a single resin bead is sufficient for sequencing by HR ESI-MS/MS experiments. The developed strategy was applied to a small training library of α chymotrypsin substrates. The obtained results confirm the applicability of the proposed method in combinatorial chemistry. Keywords Derivatization of peptides · ESI-MS/MS

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“…[52] New designs of peptide sequence protocols can be identified systematically by developing a cyclic-peptide library based on automated computer analyses of mass spectra. [94] Recently, dendritic peptide monomers have also been reported to form peptide nanotubes. For example, dendritic peptides self-assemble to form cyclic structures by hydrogen bonding the narrow ends of the peptides and spreading out of the dendritic parts (Fig.…”

Section: Peptide Nanotubes From Nonlinear Peptide Monomersmentioning

confidence: 99%

Peptide‐Based Nanotubes and Their Applications in Bionanotechnology

2005

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In nature, biological nanomaterials are synthesized under ambient conditions in a natural microscopic‐sized laboratory, such as a cell. Biological molecules, such as peptides and proteins, undergo self‐assembly processes in vivo and in vitro, and these monomers are assembled into various nanometer‐scale structures at room temperature and atmospheric pressure. The self‐assembled peptide nanostructures can be further organized to form nanowires, nanotubes, and nanoparticles via their molecular‐recognition functions. The application of molecular self‐assemblies of synthetic peptides as nanometer‐scale building blocks in devices is robust, practical, and affordable due to their advantages of reproducibility, large‐scale production ability, monodispersity, and simpler experimental methods. It is also beneficial that smart functionalities can be added at desired positions in peptide nanotubes through well‐established chemical and peptide syntheses. These features of peptide‐based nanotubes are the driving force for investigating and developing peptide nanotube assemblies for biological and non‐biological applications.

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Automated Mass Spectrometric Sequence Determination of Cyclic Peptide Library Members

Cited by 59 publications

References 46 publications

Systemic Antibacterial Activity of Novel Synthetic Cyclic Peptides

Systemic Antibacterial Activity of Novel Synthetic Cyclic Peptides

Sensitive electrospray mass spectrometry analysis of one-bead-one-compound peptide libraries labeled by quaternary ammonium salts

Peptide‐Based Nanotubes and Their Applications in Bionanotechnology

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