Characterization of cyclic peptides containing disulfide bonds

Johnson, Mindy; Liu, Mingtao; Struble, Elaine; Hettiarachchi, Kanthi

doi:10.1016/j.jpba.2015.01.009

Cited by 7 publications

(5 citation statements)

References 23 publications

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“…Cyclic peptides are usually synthesized by reacting the N-terminus with the C-terminus or by exploiting specific functional groups of certain amino acids present in the sequence. A representative example is the sulfhydryl group of cysteine-containing peptides which may cyclize through the formation of intramolecular disulfide bonds [ 39 ].…”

Section: Reviewmentioning

confidence: 99%

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

Vrettos

Mező

Tzakos

2018

Beilstein J. Org. Chem.

125

124

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Cancer is the second leading cause of death affecting nearly one in two people, and the appearance of new cases is projected to rise by >70% by 2030. To effectively combat the menace of cancer, a variety of strategies have been exploited. Among them, the development of peptide–drug conjugates (PDCs) is considered as an inextricable part of this armamentarium and is continuously explored as a viable approach to target malignant tumors. The general architecture of PDCs consists of three building blocks: the tumor-homing peptide, the cytotoxic agent and the biodegradable connecting linker. The aim of the current review is to provide a spherical perspective on the basic principles governing PDCs, as also the methodology to construct them. We aim to offer basic and integral knowledge on the rational design towards the construction of PDCs through analyzing each building block, as also to highlight the overall progress of this rapidly growing field. Therefore, we focus on several intriguing examples from the recent literature, including important PDCs that have progressed to phase III clinical trials. Last, we address possible difficulties that may emerge during the synthesis of PDCs, as also report ways to overcome them.

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Section: Reviewmentioning

confidence: 99%

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

Vrettos

Mező

Tzakos

2018

Beilstein J. Org. Chem.

125

124

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“…The purification by RP-HPLC chromatography allowed to obtain the desired cyclic peptides 7a – c with a grade of purity ≥95% in 41%, 55%, and 40% overall yields, respectively. Analysis of cyclic penta-peptides incorporating thioether bridge is tricky and complex in order to achieve a rigorous proof of structure; according to a recent paper by Johnson et al, full characterization of the final products 7a – c has been performed through MS-UPLC (Figures S1–S3), analytical RP-HPLC, and 1 H NMR.…”

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confidence: 99%

Opioid Receptor Activity and Analgesic Potency of DPDPE Peptide Analogues Containing a Xylene Bridge

Stefanucci

Novellino

Mirzaie

et al. 2017

ACS Med. Chem. Lett.

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d-Pen,d-Pen enkephalin (DPDPE) is one of the most selective synthetic peptide agonists targeting the δ-opioid receptor. Three cyclic analogues of DPDPE containing a xylene bridge in place of disulfide bond have been synthesized and fully characterized as opioid receptors agonists. The activity was investigated showing a good affinity of- for μ- and δ-receptors. biological assays revealed that is the most potent analogue with the ability to maintain high level of analgesia from 15 to 60 min following intracerebroventricular (i.c.v.) administration, whereas DPDPE was slightly active until 45 min. Compound induced long lasting analgesia also after subcutaneous administration, whereas DPDPE was inactive.

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“…Johnson et al 23 employed DTT-facilitated reduction coupled with liquid chromatography-mass spectrometry (LC-MS) analysis as a practical approach to unravel the structural composition of cyclic peptides featuring DSBs (p-Cl-Phe-DPDPE, DPDPE, and CTOP), as well as to confirm the existence or nonexistence of their linear precursor peptides. 23 DTT and TCEP play vital roles in protein biochemistry. Getz et al 25 compared the reducing properties of DTT and TCEP using myosin as a model enzyme.…”

Section: Digestion Of Proteinsmentioning

confidence: 99%

“…Dithiothreitol (DTT), tris (2‐carboxyethyl)phosphine (TCEP), performic acid, and sodium sulfite 23 are common reductants for DSB cleavage 24,25 and subsequent alkylation, which prevents the oxidation of free sulfhydryl groups of reduced proteins and peptides during enzymatic digestion before mass spectrometric analysis 26,27 . Iodoacetamide (IAM), iodoacetic acid (IAA), and N ‐ethylmaleimide (NEM) are some commonly used cysteine alkylating reagents 28,29 .…”

Section: Sample Preparation For Mass Spectrometric Analysis Of Dsbsmentioning

confidence: 99%

“…In contrast to linear peptides, the study of cyclic peptides containing disulfide links is more challenging and necessitates the use of indirect approaches to provide reliable structural confirmation. Johnson et al 23 employed DTT‐facilitated reduction coupled with liquid chromatography‐mass spectrometry (LC‐MS) analysis as a practical approach to unravel the structural composition of cyclic peptides featuring DSBs (p‐Cl‐Phe‐DPDPE, DPDPE, and CTOP), as well as to confirm the existence or nonexistence of their linear precursor peptides 23 . DTT and TCEP play vital roles in protein biochemistry.…”

Section: Sample Preparation For Mass Spectrometric Analysis Of Dsbsmentioning

confidence: 99%

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Recent advancements in disulfide bridge characterization: Insights from mass spectrometry

Chaturvedi,

Bawake,

Sharma

2024

Rapid Comm Mass Spectrometry

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RationaleDisulfide bridges (DSB) play an important role in stabilizing three‐dimensional structures of biopharmaceuticals, single purified proteins, and various cyclic peptide drugs that contain disulfide in their structures. Incorrect cross‐linking known as DSB scrambling results in misfolded structures that can be inactive, immunogenic, and susceptible to aggregation. Very few articles have been published on the experimental annotation of DSBs in proteins and cyclic peptide drugs. Accurate characterization of the disulfide bond is essential for understanding protein confirmation.MethodsCharacterizing DSBs using mass spectrometry (MS) involves the chemical and enzymatic digestion of samples to obtain smaller peptide fragments, in both reduced and nonreduced forms. Subsequently, these samples are analyzed using MS to locate the DSB, either through interpretation or by employing various software tools.ResultsThe main challenge in DSB analysis methods using sample preparation is to obtain a sample solution in which nonnative DSBs are not formed due to high pH, temperature, and presence of free sulfhydryl groups. Formation of nonnative DSBs can lead to erroneous annotation of disulfide bond. Sample preparation techniques, fragmentation methods for DSB analysis, and contemporary approaches for DSB mapping using this fragmentation were discussed.ConclusionsThis review presents the latest advancement in MS‐based characterization; also a critical perspective is presented for further annotation of DSBs using MS, primarily for single purified proteins or peptides that are densely connected and rich in cysteine. Despite significant breakthroughs resulting from advancements in MS, the analysis of disulfide bonds is not straightforward; it necessitates expertise in sample preparation and interpretation.

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Characterization of cyclic peptides containing disulfide bonds

Cited by 7 publications

References 23 publications

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

Opioid Receptor Activity and Analgesic Potency of DPDPE Peptide Analogues Containing a Xylene Bridge

Recent advancements in disulfide bridge characterization: Insights from mass spectrometry

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