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1. |
Efficient method of circumventing insolubility problems with fully protected peptide carboxylates viain situdirect thioesterification reactions |
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Journal of Peptide Science,
Volume 15,
Issue 11,
2009,
Page 693-696
Stevenson Flemer,
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摘要:
AbstractA straightforward and convenient protocol is presented for the direct thioesterification of fully protected peptideC‐terminal carboxylates synthesized by Fmoc strategy. This methodology specifically serves to overcome the frequent insolubility problem of these fully protected carboxolate isolates during the thioesterification process by carrying out the reaction as anin situprocedure on the freshly cleaved 1% TFA/DCM solution of carboxylate. The direct thioesterification of a number of insolubility prone peptide systems is explored and compared with some control systems for ease of conversion to the corresponding thioesters. It is shown that although the fully protected carboxylates are indeed insoluble to varying degrees in the thioesterification reactions carried out using the classical approach, full dissolution is maintained and complete conversion is evident using thein situmethodology. This protocol serves to remove a frequent stumbling block in the preparation of peptide thioesters via the direct approach, allowing for facile entry into previously difficult systems traditionally unapproachable through this method. Copyright © 2009 European Peptide Society and John Wiley&Sons, L
ISSN:1075-2617
DOI:10.1002/psc.1181
出版商:John Wiley&Sons, Ltd.
年代:2009
数据来源: WILEY
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2. |
Quality specifications for peptide drugs: a regulatory‐pharmaceutical approach |
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Journal of Peptide Science,
Volume 15,
Issue 11,
2009,
Page 697-710
Valentijn Vergote,
Christian Burvenich,
Christophe Van de Wiele,
Bart De Spiegeleer,
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摘要:
AbstractPeptide drugs, as all types of pharmaceuticals, require adequate specifications (i.e. quality attributes, procedures and acceptance criteria) as part of their quality assurance to ensure the safety and efficacy of drug substances (i.e. active pharmaceutical ingredients) and drug products (i.e. finished pharmaceutical dosage forms). Compendial monographs are updated regularly to keep up with the most recent advances in peptide synthesis (e.g. reduced by‐products) and analytical technology. Nevertheless, currently applied pharmacopoeial peptide specifications are barely harmonized yet (e.g. large differences between theEuropean Pharmacopoeiaand theUnited States Pharmacopeia), increasing the manufacturers' burden of performing analytical procedures in different ways, using different acceptance criteria. Additionally, the peptide monographs are not always consistent within a single pharmacopoeia. In this review, we highlight the main differences and similarities in compendial peptide specifications (including identification, purity and assay). Based on comparison, and together with additional information from peptide drug substance manufacturers and public evaluation reports on registration files of non‐pharmacopoeial peptide drugs, a consistent monograph structure is proposed. Copyright © 2009 European Peptide Society and John Wiley&Sons,
ISSN:1075-2617
DOI:10.1002/psc.1167
出版商:John Wiley&Sons, Ltd.
年代:2009
数据来源: WILEY
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3. |
Ghrelin—a novel generation of anti‐obesity drug: design, pharmacomodulation and biological activity of ghrelin analogues |
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Journal of Peptide Science,
Volume 15,
Issue 11,
2009,
Page 711-730
Constance Chollet,
Karolin Meyer,
Annette G. Beck‐Sickinger,
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摘要:
AbstractGhrelin is a unique bioactive peptide with respect to both the structure and its biological function. This 28‐amino acid peptide is modified with ann‐octanoyl group at serine‐3, and accordingly is the only lipidated biologically active peptide hormone known so far. Ghrelin binds to the so‐called ghrelin or GHS receptor, a member of the class A of G‐protein coupled receptors, which leads to Ca2+release intracellularly due to the activation of the Gq‐system. Interestingly, the ghrelin receptor shows a significant constitutive activity which means that in addition to agonists and antagonists, inverse agonists play an important role in receptor modulation. In this review, the major activities of ghrelin are summarized with a strong focus on the regulation of food intake. So far reported agonists, antagonists and inverse agonists are shown and structure activitiy relationships are discussed. Furthermore, the application of ghrelin ligands as novel anti‐obesity drugs is outlined and the state of the art in this field is summarized. Copyright © 2009 European Peptide Society and John W
ISSN:1075-2617
DOI:10.1002/psc.1177
出版商:John Wiley&Sons, Ltd.
年代:2009
数据来源: WILEY
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4. |
Synthesis of peptide thioesters via anN–Sacyl shift reaction under mild acidic conditions on anN‐4,5‐dimethoxy‐2‐mercaptobenzyl auxiliary group |
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Journal of Peptide Science,
Volume 15,
Issue 11,
2009,
Page 731-737
Ken'ichiroh Nakamura,
Tomoki Kanao,
Tomoya Uesugi,
Toshiaki Hara,
Takeshi Sato,
Toru Kawakami,
Saburo Aimoto,
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摘要:
AbstractAn efficient method of peptide thioester synthesis is described. The reaction is based on anN‐4,5‐dimethoxy‐2‐mercaptobenzyl (Dmmb) auxiliary‐assistedN‐Sacyl shift reaction after assembling a peptide chain by Fmoc‐solid phase peptide synthesis. The Dmmb‐assistedN‐Sacyl shift reaction proceeded efficiently under mildly acidic conditions, and the peptide thioester was obtained by treating the resultingS‐peptide with sodium 2‐mercaptoethanesulfonate. No detectable epimerization of the amino acid residue adjacent to the thioester moiety in the case of Leu was found. The reactions were also amenable to the on‐resin preparation of peptide thioesters. The utility was demonstrated by the synthesis of a 41‐mer peptide thioester, a phosphorylated peptide thioester and a 33‐mer peptide thioester containing a trimethylated lysine residue. Copyright © 2009 European Peptide Soci
ISSN:1075-2617
DOI:10.1002/psc.1164
出版商:John Wiley&Sons, Ltd.
年代:2009
数据来源: WILEY
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5. |
The inherent flexibility of peptides and protein fragments quantitized by CD in conjunction with CCA+ |
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Journal of Peptide Science,
Volume 15,
Issue 11,
2009,
Page 738-752
Imre Jákli,
András Perczel,
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摘要:
AbstractECD spectroscopy is traditionally used for rapid, non‐atomic level structure analysis of natural products such as peptides and proteins. Unlike globular proteins, peptides less frequently adopt a single 3D‐fold in a time average manner. Moreover, they exhibit an ensemble of conformers composed of a multitude of substantially different structures. In principle, both ECD‐ and vibrational circular dichroism (VCD)‐spectroscopy are sensitive enough to pick up structural information on these dynamic ensembles. However, the interpretation of the raw spectral data of these highly dynamic molecular systems can be cumbersome. The herein presentedConvexConstraintAnalysis Plus method, or CCA+ for short (http://www.chem.elte.hu/departments/protnmr/cca/), provides a unique opportunity for spectral ensemble analysis of peptides, glycopeptides, peptidomimetics, and other foldamers. The precision and accuracy of the approach is presented here through different peptide model systems. An interesting temperature and pH dependent folding and unfolding of a miniprotein (e.g. Tc5b variant) is also described. Analysis of CD spectra sets strongly affected by solvent and ion type is also introduced to account for severe environmental‐induced structure influencing effect(s). The deconvolution makes always possible the quantitative data analysis even when the interpretation of the deconvolution resulted in pure CD curves is complex. Copyright © 2009 European Peptide Society and John Wiley
ISSN:1075-2617
DOI:10.1002/psc.1169
出版商:John Wiley&Sons, Ltd.
年代:2009
数据来源: WILEY
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6. |
Modifying the conservedC‐terminal tyrosine of the peptide hormone PYY3‐36 to improve Y2 receptor selectivity |
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Journal of Peptide Science,
Volume 15,
Issue 11,
2009,
Page 753-759
Søren L. Pedersen,
Birgitte Holst,
Niels Vrang,
Knud J. Jensen,
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摘要:
AbstractThe Y2 selective PYY derived peptide PYY3‐36 was recently shown to play a role in appetite regulation. Novel PYY3‐36 analogs with high selectivity for the Y2 receptor could be potential drug candidates for the treatment of obesity. TheC‐terminal pentapeptide segment of PYY3‐36 is believed to bind to the Y receptors. Tyr‐36 is highly conserved across species and only few successful modifications of Tyr‐36 have been documented. PYY3‐36 analogs were prepared using solid‐phase peptide chemistry and tested for binding to the Y1, Y2 and Y4 receptor subtypes by radioligand displacement assay. The Y2 receptor agonists with the best affinity and selectivity were further investigated for activity towards the Y1 and Y2 receptor subtypes. Unexpectedly, modifications of Tyr‐36 were well‐tolerated, and the analogs of PYY3‐36 in which the Tyr‐36 hydroxyl group was substituted with a halogen or an amino group were particularly well tolerated and yielded an improved selectivity and approximately equipotent affinity to the Y2 receptor. These modifications could be used to design new potential drug candidates for the treatment of obesity. Copyright © 2009 European Peptide Society
ISSN:1075-2617
DOI:10.1002/psc.1170
出版商:John Wiley&Sons, Ltd.
年代:2009
数据来源: WILEY
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7. |
Incorporation ofN‐amidino‐pyroglutamic acid into peptides using intramolecular cyclization of α‐guanidinoglutaric acid |
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Journal of Peptide Science,
Volume 15,
Issue 11,
2009,
Page 760-766
Sergey Burov,
Yulia Moskalenko,
Marina Dorosh,
Zoya Shkarubskaya,
Evgeny Panarin,
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摘要:
AbstractN‐terminal modification of peptides by unnatural amino acids significantly affects their enzymatic stability, conformational properties and biological activity. Application ofN‐amidino‐amino acids, positively charged under physiological conditions, can change peptide conformation and its affinity to the corresponding receptor. In this article, we describe synthesis of short peptides, containing a new building block—N‐amidino‐pyroglutamic acid. Although direct guanidinylation of pyroglutamic acid and oxidation ofN‐amidino‐proline using RuO4did not produce positive results,N‐amidino‐Glp‐Phe‐OH was synthesized on Wang polymer by cyclization of α‐guanidinoglutaric acid residue. In the course of synthesis, it was found that literature procedure of selective Boc deprotection using TMSOTf/TEA reagent is accompanied by concomitant side reaction of triethylamine alkylation by polymer linker fragment. It should be mentioned that independently from cyclization time and coupling agent (DIC or HCTU), the lactam formation was incomplete. Separation of the cyclic product from the linear precursor was achieved by HPLC in ammonium formate buffer at pH 6. HPLC analysis showedN‐amidino‐Glp‐Phe‐OH stability at acidic and physiological pH and fast ring opening in water solution at pH 9. The suggested method ofN‐amidino‐Glp residue formation can be applied in the case of short peptide chains, whereas synthesis of longer ones will require fragment condensation approach. Copyright © 2009 European P
ISSN:1075-2617
DOI:10.1002/psc.1171
出版商:John Wiley&Sons, Ltd.
年代:2009
数据来源: WILEY
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8. |
Local formation of angiotensin peptides with paracrine activity by adipocytes |
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Journal of Peptide Science,
Volume 15,
Issue 11,
2009,
Page 767-776
Felix Weiland,
Eugen J. Verspohl,
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摘要:
AbstractA local paracrine angiotensin (ANG) system influences the insulin sensitivity and cell differentiation of adipose tissue. The limited view of a merely systemic renin‐angiotensin‐aldosterone‐system with ANG II (1–8) as the main mediator of ANG‐related effects may oversimplify the situation. The aim was to analyze the degradation of ANG by using capillary electrophoresis (CE) techniques. The supernatant of cultured 3T3‐L1 adipocytes was used directly, and some data on degraded peptides were combined with a biological effect. The formation of several peptides such as ANG II (1–8), —III (2–8), —IV (3–8), and ANG (1–7) as degradation products is demonstrated; in addition low levels of ANG (3–7) are identified. The concentrations of the peptides ANG III (2–8) and ANG IV (3–8) (both are AT4receptor agonists) are modified in the vicinity of adipose tissue cells by amino‐terminal degradation which resulted in ANG (3–8), —(4–8) and —(5–8). ANG IV (3–8) and ANG II (1–8) were biologically highly effective in inhibiting IRAP (insulin regulated aminopeptidase, part of the AT4receptor). It is observed that ANG (1–7) is the main degradation product derived from ANG I via ANG (1–9) and that ANG III (2–8) is one important regulated peptide for IRAP. Copyright © 20
ISSN:1075-2617
DOI:10.1002/psc.1174
出版商:John Wiley&Sons, Ltd.
年代:2009
数据来源: WILEY
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9. |
Synthesis and receptor binding of opioid peptide analogues containing β3‐homo‐amino acids |
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Journal of Peptide Science,
Volume 15,
Issue 11,
2009,
Page 777-782
Dominika Wilczyńska,
Piotr Kosson,
Maria Kwasiborska,
Andrzej Ejchart,
Aleksandra Olma,
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摘要:
Abstractβ‐Amino acids containing hybrid peptides and β‐peptides show great potential as peptidomimetics. In this paper we describe the synthesis and affinity toward the µ‐ and δ‐opioid receptors of β‐peptides, analogues of Leu‐enkephalin, deltorphin I, dermorphin and α,β‐hybrides, analogues of deltorphin I. Substitution of α‐amino acid residues with β3‐homo‐amino acid residues, in general resulted in decrease of affinity to opioid receptors. However, the incorporation β3h‐D‐Ala in position 2 or β3hPhe in position 3 of deltorphin I resulted in potent and selective ligand for δ‐opioid receptor. The NMR studies of β‐deltorphin I analogue suggest that conformational motions in the central part of the peptide backbone are partially restricted and some conformational preferences can be expected. Copyright © 2009 European
ISSN:1075-2617
DOI:10.1002/psc.1175
出版商:John Wiley&Sons, Ltd.
年代:2009
数据来源: WILEY
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10. |
Receptor assay guided structure‐activity studies of helicokinin insect neuropeptides and peptidomimetic analogues |
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Journal of Peptide Science,
Volume 15,
Issue 11,
2009,
Page 783-789
Jürgen Scherkenbeck,
Horst‐Peter Antonicek,
Kathrin Vogelsang,
Tino Zdobinsky,
Karin Brücher,
Denise Rehländer,
Heru Chen,
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摘要:
AbstractNeuropeptides control numerous physiological processes in insects. The regulation of water balance is a crucial aspect of homeostasis in terrestrial insects and has been shown to be under endocrine control, primarily by corticotrophin releasing factor (CRF)‐related peptides and kinins. For helicokinin I, a diuretic neuropeptide from the economically important insect pestHeliothis virescens, detailed structure‐activity relationships have been established based on truncated structures, diverse amino acid scans and peptidomimetic analogues. The activities of selected compounds on functional expressed helicokinin receptors are compared with the results of a Malphigian tubule assay. Implications for further peptidomimetic variations are provided. Copyright © 2009 European Peptide Society and John Wiley&Sons,
ISSN:1075-2617
DOI:10.1002/psc.1176
出版商:John Wiley&Sons, Ltd.
年代:2009
数据来源: WILEY
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