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1. |
Josef Rudinger Memorial Lecture: Use of peptides to modulate protein‐protein interactions |
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Journal of Peptide Science,
Volume 21,
Issue 6,
2015,
Page 447-453
Ernest Giralt,
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摘要:
Peptides are destined to play a major role as therapeutic agents. My laboratory is contributing to speeding up this process. On the one hand, we devote efforts to studying the molecular details and dynamics of the events that occur during molecular recognition at protein surfaces. We succeeded to design and synthesize peptides able to modulate these recognition events either permanently or in response to light. On the other hand, we are discovering and designing peptides able to cross biological barriers. Our aim is to use these peptides as shuttles for targeting therapeutic agents to organs, tissues, or cells, with a special emphasis on drug delivery to the brain. Copyright © 2015 European Peptide Society and John Wiley&Sons, Ltd
ISSN:1075-2617
DOI:10.1002/psc.2768
年代:2015
数据来源: WILEY
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2. |
Microwave‐assisted solid‐phase peptide synthesis of neurosecretory protein GL composed of 80 amino acid residues |
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Journal of Peptide Science,
Volume 21,
Issue 6,
2015,
Page 454-460
Keiko Masuda,
Haruka Ooyama,
Kenshiro Shikano,
Kunihiro Kondo,
Megumi Furumitsu,
Eiko Iwakoshi‐Ukena,
Kazuyoshi Ukena,
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摘要:
We recently identified a novel cDNA encoding a small secretory protein of 80 amino acid residues, termed neurosecretory protein GL (NPGL), from the chicken hypothalamus. Homologs of NPGL have been reported to be present in mammals, such as human and rat. NPGL is amidated at its C‐terminus, contains an intramolecular disulfide bond, and is hydrophobic in nature. In this study, we have optimized the synthesis of the entire 80‐amino acid peptide sequence of rat NPGL by microwave‐assisted solid‐phase peptide synthesis. NPGL was obtained with a 10% yield when the coupling reactions were performed using 1‐[Bis(dimethylamino)methylene]‐1H‐1,2,3‐triazolo[4,5‐b]pyridinium‐3‐oxid hexafluorophosphate (HATU) at 50 °C for 5 min, and Fmoc deprotections were performed using 40% piperidine containing 0.1 M HOBt. Furthermore, the disulfide bond of NPGL was formed with 20% yield with the use of glutathione‐containing redox buffer and 50% acetonitrile. Copyright © 2015 European Peptide S
ISSN:1075-2617
DOI:10.1002/psc.2756
年代:2015
数据来源: WILEY
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3. |
Synthesis of ‘head‐to‐tail’ cyclized peptides on solid support using a chelating amide as new orthogonal protecting group |
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Journal of Peptide Science,
Volume 21,
Issue 6,
2015,
Page 461-466
Myriam Lay,
Willi Bannwarth,
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摘要:
The synthesis of ‘head‐to‐tail’ cyclized peptides requires orthogonal protecting groups. Herein, we report on the introduction of bis(2‐pyridylmethyl)amine (Bpa) as a new protecting group for carboxylic functions in SPPS. The synthesis of the Bpa‐protected aspartic acid was straightforward, and its utility was investigated under standard peptide synthesis conditions. The new protecting group was cleaved in a very mild way using Cu(OAc)2and 2‐(trimethylsilyl)ethanol as nucleophile in a microwave oven without affecting other groups. Hence, the new group is ideally suited for the synthesis of ‘head‐to‐tail’ cyclic peptides, as demonstrated for a cyclic pentapeptide and cyclic hexapeptides. Copyright © 2015 European Peptide Society an
ISSN:1075-2617
DOI:10.1002/psc.2758
年代:2015
数据来源: WILEY
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4. |
N‐terminal guanidinylation of the cyclic 1,4‐ureido‐deltorphin analogues: the synthesis, receptor binding studies, and resistance to proteolytic digestion |
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Journal of Peptide Science,
Volume 21,
Issue 6,
2015,
Page 467-475
Krzysztof Bańkowski,
Olga M. Michalak,
Anna Leśniak,
Katarzyna E. Filip,
Piotr Cmoch,
Zbigniew Szewczuk,
Piotr Stefanowicz,
Jan Izdebski,
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摘要:
The synthesis of a series ofN‐guanidinylated cyclic ureidopeptides, analogues of 1,4‐ureido‐deltorphin/dermorphine tetrapeptide is described. The δ‐ and μ‐opioid receptor affinity of new guanidinylated analogues and their non‐guanidinylated precursors was determined by the displacement radioligand binding experiments. Our results indicate that the guanidinylation of cyclic 1,4‐ureidodeltorphin peptide analogues does not exhibit a uniform influence on the opioid receptor binding properties, similarly as reported earlier for some linear peptides. All analogues were also tested for theirin vitroresistance to proteolysis during incubation with large excess of chymotrypsin, pepsin, and papain by means of mass spectroscopy. Guanidinylated ureidopeptides1G–4Gshowed mixed μ agonist/δ agonist properties and high enzymatic stability indicating their potential as therapeutic agents for treatment of pain. Copyright © 2015 European Peptide Society and
ISSN:1075-2617
DOI:10.1002/psc.2762
年代:2015
数据来源: WILEY
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5. |
The crystal structure of Z‐Gly‐Aib‐Gly‐Aib‐OtBu |
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Journal of Peptide Science,
Volume 21,
Issue 6,
2015,
Page 476-479
Renate Gessmann,
Hans Brückner,
Michalis Aivaliotis,
Kyriacos Petratos,
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摘要:
The synthetic peptide Z‐Gly‐Aib‐Gly‐Aib‐OtBu was dissolved in methanol and crystallized in a mixture of ethyl acetate and petroleum ether. The crystals belong to the centrosymmetric space groupP4/nthat is observed less than 0.3% in the Cambridge Structural Database. The first Gly residue assumes a semi‐extended conformation (φ±62°,ψ∓131°). The right‐handed peptide folds in two consecutiveβ‐turns of type II' and type I or an incipient 310‐helix, and the left‐handed counterpart folds accordingly in the opposite configuration. In the crystal lattice, one molecule is linked to four neighbors in theab‐plane via hydrogen bonds. These bonds form a continuous network of left‐ and right‐handed molecules. The successiveab‐planes stack via apolar contacts in thec‐direction. An ethyl acetate molecule is situated on and close to the fourfold axis. Copyright © 2015 European Pe
ISSN:1075-2617
DOI:10.1002/psc.2764
年代:2015
数据来源: WILEY
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6. |
One short cysteine‐rich sequence pattern – two different disulfide‐bonded structures – a molecular dynamics simulation study |
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Journal of Peptide Science,
Volume 21,
Issue 6,
2015,
Page 480-494
Sonja A. Dames,
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摘要:
The nematocyst walls ofHydraare formed by proteins containing small cysteine‐rich domains (CRDs) of ~25 amino acids. The first CRD of nematocyst outer all antigen (NW1) and the C‐terminal CRD of minicollagen‐1 (Mcol1C) contain six cysteines at identical sequence positions, however adopt different disulfide bonded structures. NW1 shows the disulfide connectivities C2‐C14/C6‐C19/C10‐C18 and Mcol1C C2‐C18/C6‐C14/C10‐C19. To analyze if both show structural preferences in the open, non‐disulfide bonded form, which explain the formation of either disulfide connectivity pattern, molecular dynamics (MD) simulations at different temperatures were performed. NW1 maintained in the 100‐ns MD simulations at 283 K a rather compact fold that is stabilized by specific hydrogen bonds. The Mcol1C structure fluctuated overall more, however stayed most of the time also rather compact. The analysis of the backbone Φ/ψ angles indicated different turn propensities for NW1 and Mcol1C, which mostly can be explained based on published data about the influence of different amino acid side chains on the local backbone conformation. Whereas a folded precursor mechanism may be considered for NW1, Mcol1C may fold according to the quasi‐stochastic folding model involving disulfide bond reshuffling and conformational changes, locking the native disulfide conformations. The study further demonstrates the power of MD simulations to detect local structural preferences in rather dynamic systems such as the open, non‐disulfide bonded forms of NW1 and Mcol1C, which complement published information from NMR backbone residual dipolar couplings. Because the backbone structural preferences encoded by the amino acid sequence embedding the cysteines influence which disulfide connectivities are formed, the data are generally interesting for a better understanding of oxidative folding and the design of disulfide stabilized therapeutics. Copyright © 2015 European Peptide So
ISSN:1075-2617
DOI:10.1002/psc.2765
年代:2015
数据来源: WILEY
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7. |
Conformational and biological properties ofBauhinia bauhinioideskallikrein inhibitor fragments with bradykinin‐like activities |
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Journal of Peptide Science,
Volume 21,
Issue 6,
2015,
Page 495-500
Flávio Lopes Alves,
Maria Luiza Vilela Oliva,
Antonio Miranda,
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摘要:
Proteinase inhibitors extracted form medicinal plants are an interesting source of new drugs. Modifications in the structure of some of this kind of macromolecules could also lead to compounds of interesting biological properties. In this work, we synthesized and tested one fragment containing the reactive site of theBauhinia bauhinioides kallikrein inhibitor(BbKI), denoted BbKI51–62, and a related analog (P2) in which a proline residue was inserted in order to mimic the N‐terminal region of the bradykinin molecule. The related retro‐inverso counterparts Ri‐BbKI51–62and Ri‐P2were also included. The ability of these peptides to induce contraction of stomach fundus isolated from mouse was evaluated as well as their capability to induce calcium release from a cell culture of smooth muscle from guinea pig ileum. The conformational properties of the peptides were evaluated by circular dichroism and their resistance to enzymatic degradation by exposure to human blood plasma. Our results show that neither the parent BbKI51–62nor its Ri‐BbKI51–62analog exhibit bradykinin‐like activity, although the retro‐inverso isomer was resistant to blood plasma degradation. On the other hand, the peptides P2and Ri‐P2presented contractile activities on gastric smooth muscle from stomach fundus possibly by acting via B‐2 receptor. Both compounds also induce calcium release from guinea pig ileum muscle cells in a manner similar to bradykinin. Moreover, both compounds also inhibited porcine pancreatic kallikrein. However, conformational analysis did not reveal any direct correlation between structure and biological effects. Copyright © 2015 European Peptide Societ
ISSN:1075-2617
DOI:10.1002/psc.2766
年代:2015
数据来源: WILEY
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8. |
Engineering of a linear inactive analog of human β‐defensin 4 to generate peptides with potent antimicrobial activity |
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Journal of Peptide Science,
Volume 21,
Issue 6,
2015,
Page 501-511
Himanshu Sharma,
Basil Mathew,
Ramakrishnan Nagaraj,
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摘要:
Human β‐defensins (HBDs) are cationic antimicrobial peptides constrained by three disulfide bridges. They have diverse range of functions in the innate immune response. It is of interest to investigate whether linear analogs of defensins can be generated, which possess antimicrobial activity. In this study, we have designed linear peptides with potent antimicrobial activity from an inactive peptide spanning the N‐terminus of HBD4. Our results show thatl‐arginine tod‐arginine substitution imparts considerable antimicrobial activity against both bacteria andCandida albicans. Increase in hydrophobicity by fatty acylation of the peptides with myristic acid further enhances their potency. In the presence of high concentrations of salt, antimicrobial activity of the myristoylated peptide withl‐arginine is attenuated relatively to a lesser extent as compared with the linear active peptide withd‐arginine. Substitution of cysteine with the hydrophobic helix‐promoting amino acid α‐aminoisobutyric acid favors candidacidal activity but not antibacterial activity. The mechanism of killing byd‐arginine substituted unacylated analog involves transient interaction with the bacterial membrane followed by translocation into the cytoplasm without membrane permeabilization. Accumulation of peptides in the cytoplasm can affect various cellular processes that lead to cell death. However, the peptide causes membrane permeabilization in case ofC. albicans. Myristoylation results in greater interaction of the peptide chain with the microbial cell surface and causes membrane permeabilization. Results described in the study demonstrate that it is possible to generate highly active linear analogs of defensins by selective introduction ofd‐amino acids and fatty acids, which could be attractive candidates for development as therapeutic agents. Copyright © 2015 European Peptide Society
ISSN:1075-2617
DOI:10.1002/psc.2770
年代:2015
数据来源: WILEY
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9. |
Antimicrobial benzodiazepine‐based short cationic peptidomimetics |
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Journal of Peptide Science,
Volume 21,
Issue 6,
2015,
Page 512-519
Galina M. Zats,
Marina Kovaliov,
Amnon Albeck,
Shimon Shatzmiller,
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摘要:
Antimicrobial peptides (AMPs) appear to be good candidates for the development of new antibiotic drugs. We describe here the synthesis of peptidomimetic compounds that are based on a benzodiazepine scaffold flanked with positively charged and hydrophobic amino acids. These compounds mimic the essential properties of cationic AMPs. The new design possesses the benzodiazepine scaffold that is comprised of two glycine amino acids and which confers flexibility and aromatic hydrophobic ‘back’, and two arms used for further synthesis on solid phase for incorporation of charged and hydrophobic amino acids. This approach allowed us a better understanding of the influence of these features on the antimicrobial activity and selectivity. A novel compound was discovered which has MICs of 12.5 µg/ml against Staphylococcus aureus and 25 µg/ml against Escherichia coli, similar to the well‐known antimicrobial peptide MSI‐78. In contrast to MSI‐78, the above mentioned compound has lower lytic effect against mammalian red blood cells. These peptidomimetic compounds will pave the way for future design of potent synthetic mimics of AMPs for therapeutic and biomedical applications. Copyright © 2015 European Peptide Society and John
ISSN:1075-2617
DOI:10.1002/psc.2771
年代:2015
数据来源: WILEY
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10. |
Issue information |
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Journal of Peptide Science,
Volume 21,
Issue 6,
2015,
Page -
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ISSN:1075-2617
DOI:10.1002/psc.2695
年代:2015
数据来源: WILEY
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