|
1. |
Intraoral administration of a T‐cell epitope peptide induces immunological tolerance in Cry j 2‐sensitized mice |
|
Journal of Peptide Science,
Volume 13,
Issue 8,
2007,
Page 499-503
Tomomi Yoshitomi,
Yasuhiro Nakagami,
Kazuki Hirahara,
Yoshifumi Taniguchi,
Masahiro Sakaguchi,
Makoto Yamashita,
Preview
|
PDF (148KB)
|
|
摘要:
AbstractSublingual immunotherapy using allergen‐derived peptides is feasible as a novel specific immunotherapy, but its efficacy has not yet been demonstrated in either humans or animals. In addition, it remains obscure whether the oral immune system is involved in the mechanism of sublingual immunotherapy. Here, we show that the intraoral administration of the T‐cell epitope peptide P2‐246‐259 derived from Cry j 2, a major Japanese cedar (Cryptomeria japonica) pollen allergen, to Cry j 2‐sensitized mice induces immunological tolerance, and thatex vivolymph node cell proliferation to P2‐246‐259 and Cry j 2 was inhibited. In addition, intraoral administration was shown to be superior to intragastric administration in terms of tolerance induction, suggesting that the oral immune system contributes to the induction of immunological tolerance. Therefore, the significant efficacy of sublingual immunotherapy using a peptide on allergen‐specific T‐cells was demonstrated in animals, and this may be potentiated by the oral mucosal immune system. Copyright © 2007 European Peptide Society and Jo
ISSN:1075-2617
DOI:10.1002/psc.869
出版商:John Wiley&Sons, Ltd.
年代:2007
数据来源: WILEY
|
2. |
Structure–function relationship studies of PTH(1–11) analogues containing sterically hindered dipeptide mimetics |
|
Journal of Peptide Science,
Volume 13,
Issue 8,
2007,
Page 504-512
Nereo Fiori,
Andrea Caporale,
Elisabetta Schievano,
Stefano Mammi,
Armin Geyer,
Peter Tremmel,
Angela Wittelsberger,
Iwona Woznica,
Michael Chorev,
Evaristo Peggion,
Preview
|
|
摘要:
AbstractTheN‐terminal 1–34 fragment of parathyroid hormone (PTH) is fully activein vitroandin vivoand reproduces all biological responses characteristic of the native intact PTH. In order to develop safer and non‐parenteral PTH‐like bone anabolic agents, we have studied the effect of introducing conformationally constrained dipeptide mimetics into theN‐terminal portion of PTH in an effort to generate miniaturized PTH‐mimetics. To this end, we have synthesized and conformationally and biologically characterized PTH(1–11) analogues containing 3R‐carboxy‐6S‐amino‐7,5‐bicyclic thiazolidinlactam (7,5‐bTL), a rigidified dipeptide mimetic unit. The wild type sequence of PTH(1–11) is H‐Ser‐Val‐Ser‐Glu‐Ile‐Gln‐Leu‐Met‐His‐Asn‐Leu‐NH2. The following pseudo‐undecapeptides were prepared: [Ala1, 7,5‐bTL3, 4, Nle8, Arg11]hPTH(1–11)NH2(I); [Ala1, 7,5‐bTL6, 7, Nle8, Arg11]hPTH(1–11)NH2(II); [Ala1, Nle8, 7,5‐bTL9, 10, Arg11]hPTH(1–11)NH2(III). In aqueous solution containing 20% TFE, only analogueIexhibited the typical CD pattern of the α‐helical conformation. NMR experiments and molecular dynamics calculations located the α‐helical stretch in the sequence Ile5‐His9. The dipeptide mimetic unit 7,5‐bTL induces a type III β‐turn, occupying the positionsi− 1 andiof the turn. AnalogueIIexhibited an equilibrium between a type I β‐turn and an α‐helix, and analogueIIIdid not show any ordered structure. Biological tests revealed poor activity for all analogues (EC50>0.1 mM). Apparently, the relative side‐chain orientation of Val2, Ile5and Met8can be critical for effective analogue‐receptor interaction. Considering helicity as an essential property to obtain active PTH agonists, one must decorate the correctly positioned dipeptide mimetic azabicycloalkane scaffold with substitutions corresponding to the
ISSN:1075-2617
DOI:10.1002/psc.872
出版商:John Wiley&Sons, Ltd.
年代:2007
数据来源: WILEY
|
3. |
Interaction of ACTH synthetic fragments with rat adrenal cortex membranes |
|
Journal of Peptide Science,
Volume 13,
Issue 8,
2007,
Page 513-518
Yulia A. Kovalitskaya,
Yury A. Zolotarev,
Alexander A. Kolobov,
Vladimir B. Sadovnikov,
Vladimir V. Yurovsky,
Elena V. Navolotskaya,
Preview
|
PDF (138KB)
|
|
摘要:
AbstractSynthetic peptide, corresponding to the amino acid sequence 11–24 of human adrenocorticotropic hormone (ACTH), was labeled with tritium (specific activity of 22 Ci/mmol). [3H]ACTH (11–24) was found to bind to rat adrenal cortex membranes with high affinity and specificity (Kd= 1.8 ± 0.1 nM). Twenty nine fragments of ACTH (11–24) have been synthesized and their ability to inhibit the specific binding of [3H]ACTH (11–24) to adrenocortical membranes has been investigated. Unlabeled fragment ACTH 15–18 (KKRR) was found to replace in a concentration‐dependent manner [3H]ACTH (11–24) in the receptor–ligand complex (Ki= 2.3 ± 0.2 nM). ACTH (15–18) was labeled with tritium (specific activity of 20 Ci/mmol). [3H]ACTH (15–18) was found to bind to rat adrenal cortex membranes with high affinity (Kd= 2.1 ± 0.1 nM). The specific binding of [3H]ACTH (15–18) was inhibited by unlabeled ACTH (11–24) (Ki= 2.2 ± 0.1 nM). ACTH (15–18) at the concentration range of 1–1000 nMdid not affect the adenylate cyclase activity in adrenocortical membranes. Copyright © 2007 European Peptide
ISSN:1075-2617
DOI:10.1002/psc.873
出版商:John Wiley&Sons, Ltd.
年代:2007
数据来源: WILEY
|
4. |
Ureido group containing cyclic dermorphin(1–7) analogues: synthesis, biology and conformation |
|
Journal of Peptide Science,
Volume 13,
Issue 8,
2007,
Page 519-528
Ewa Witkowska,
MichaŁ Nowakowski,
Marta Oleszczuk,
Katarzyna Filip,
MaŁgorzata Ciszewska,
Nga N. Chung,
Peter W. Schiller,
Jacek Wójcik,
Jan Izdebski,
Preview
|
PDF (359KB)
|
|
摘要:
AbstractSix cyclic peptides related to dermorphin(1–7) have been synthesized. The synthesis of linear peptides containing diamino acid residues in positions 2 and 4 was carried out on a 4‐methylbenzhydrylamine resin, and cyclization was achieved by treatment with bis‐(4‐nitrophenyl)carbonate to form a urea unit. The peptides were tested in the guinea‐pig ileum (GPI) and mouse vas deferens (MVD) assays. Diverse opioid agonist activities were observed, depending on the size of the ring. The results were compared with those obtained earlier for 1–4 dermorphin analogues. The conformations of all six dermorphin analogues were studied. The conformational space of the peptides was examined using the electrostatically driven Monte Carlo method. On the basis of NMR data, an ensemble of conformations was obtained for each peptide. The opioid activity profiles of the compounds are discussed in the light of the structural data. Copyright © 2007 European Peptide Society and John Wil
ISSN:1075-2617
DOI:10.1002/psc.877
出版商:John Wiley&Sons, Ltd.
年代:2007
数据来源: WILEY
|
5. |
Cathelicidin‐derived Trp/Pro‐rich antimicrobial peptides with lysine peptoid residue (Nlys): therapeutic index and plausible mode of action |
|
Journal of Peptide Science,
Volume 13,
Issue 8,
2007,
Page 529-535
Wan Long Zhu,
Kyung–Soo Hahm,
Song Yub Shin,
Preview
|
PDF (346KB)
|
|
摘要:
AbstractRecently, we designed a novel cell‐selective antimicrobial peptide (TPk) with intracellular mode of action from Pro → Nlys (Lys peptoid residue) substitution in a noncell‐selective cathelicidin‐derived Trp/Pro‐rich antimicrobial peptide, tritrpticin‐amide (TP; VRRFPWWWPFLRR‐NH2) (Biochemistry2006; 45: 13007–13017). In this study, to elucidate the effect of Pro → Nlys substitution on therapeutic index and mode of action of other noncell‐selective cathelicidin‐derived Trp/Pro‐rich antimicrobial peptides and develop novel short antimicrobial peptides with high cell selectivity/therapeutic index, we synthesized Nlys‐substituted antimicrobial peptides, TPk, STPk and INk, in which all proline residues of TP, symmetric TP‐analogue (STP; KKFPWWWPFKK‐NH2) and indolicidin (IN; ILPWKWPWWPWRR‐NH2) were replaced by Nlys, respectively. Compared to parent Pro‐containing peptides (TP, STP and IN), Nlys substituted peptides (TPk, STPk and Ink) had 4‐ to 26‐fold higher cell selectivity/therapeutic index. Parent Pro‐containing peptides induced a significant depolarization of the cytoplasmic membrane of intactStaphylococcus aureusat their MIC, whereas Nlys‐substituted antimicrobial peptides did not cause visible membrane depolarization at their MIC. These results suggest that the antibacterial action of Nlys‐substituted peptides is probably not due to the disruption of bacterial cytoplasmic membranes but the inhibition of intracellular components. Taken together, our results showed that Pro → Nlys substitution in other noncell‐selective Trp/Pro‐rich antimicrobial peptides such as STP and IN as well as TP can improve the cell selectivity/therapeutic index and change the mode of antibacterial action from membrane‐disrupting to intracellular targeting. In conclusion, our findings suggested that Pro → Nlys substitution in noncell‐selective Trp/Pro‐rich antimicrobial peptides is a promising method to develop cell‐selective antimicrobial peptides with intracellular target mechanism. Copyrig
ISSN:1075-2617
DOI:10.1002/psc.882
出版商:John Wiley&Sons, Ltd.
年代:2007
数据来源: WILEY
|
6. |
An enormously active and selective azapeptide inhibitor of cathepsin B |
|
Journal of Peptide Science,
Volume 13,
Issue 8,
2007,
Page 536-543
Ewa Wieczerzak,
Sylwia Rodziewicz‐Motowidło,
Elżbieta Jankowska,
Artur Giełdoń,
Jerzy Ciarkowski,
Preview
|
|
摘要:
AbstractThe peptidomimetic Z‐Arg‐Leu‐Arg‐Agly‐Ile‐Val‐OMe (where Agly means α‐aza‐glycyl, ‐NHNHCO‐) is the strongest (Ki= 480 pM) and the most selective inhibitor of cathepsin B to date, being ∼2310 times as active to cathepsin B as to cathepsin K. In this paper we introduce the peptide and seek to rationalize its structure‐activity relationships using molecular dynamics (MD) and NMR. It is shown that the ‐Agly‐moiety restrains the peptide backbone to a bent shape, contrary to its parent peptide (with Gly in position 4), having its backbone extended and flexible. This fold is maintained in the plug covalently bound to the cathepsin B Cys29, in compliance with similar bends already observed in two other azapeptides attached to the active sites of cathepsin B. The MD simulation of the Z‐Arg‐Leu‐Arg‐Agly ∼ cathepsin B complex suggests that, contrary to other potent inhibitors of cathepsin B, the current double Arg1/Arg3inhibitor, while maintaining the fold is able to form a unique ion cluster involving both Arg residues on the inhibitor part and two acidic Glu171 and Glu245 on the cathepsin B part, thus enhancing the affinity and subsequently the inhibiting power and selectivity of Z‐Arg‐Leu‐Arg‐Agly‐Ile‐Val‐OMe to the observed extreme extent. Copyright ©
ISSN:1075-2617
DOI:10.1002/psc.883
出版商:John Wiley&Sons, Ltd.
年代:2007
数据来源: WILEY
|
7. |
Substance P analogs containing α,α‐dialkylated amino acids with potent anticancer activity |
|
Journal of Peptide Science,
Volume 13,
Issue 8,
2007,
Page 544-548
Sudhanand Prasad,
Archna Mathur,
Manu Jaggi,
Anu T. Singh,
Rama Mukherjee,
Preview
|
PDF (103KB)
|
|
摘要:
AbstractSix analogs (peptides1–6) of the potent substance P (SP) derivative known as ‘Antagonist D’ were synthesized by substituting constrained amino acids Aib or Acp (cycloleucine, 1‐amino cyclopentane carboxylic acid) at different positions in the Antagonist D sequence:D‐Arg1‐Pro2‐Lys3‐Pro4‐D‐Phe5‐Gln6‐D‐Trp7‐Phe8‐D‐Trp9‐Leu10‐Leu11‐NH2. In the preliminaryin vitroantiproliferative screening of the analogs on different human cancer cell lines by 3–(4,5–dimethylthiazol–2–yl)–2,5–diphenyltetrazolium bromide (MTT) assay, peptide1was found to be the most active. Further, peptide1was butanoylated (analog5) or octanoylated (analog6) at theN‐terminus. SP analogs1, 5, and6were evaluatedin vivoin a xenograft model of human primary colon tumor (PTC) cell line in athymic nude mice and were found to cause tumor regression. This study investigates if the use of the constrained amino acids Aib and Acp in the designed SP analogs can retain thein vitroandin vivoanticancer activities, which could be useful in cancer therapy and drug targeting. Further, the strategy of incorporation of Aib or Acp in biologically active peptides can be exploited in determining the receptor‐bound conformation and in transforming these bioactive peptides into pharmacologically useful drugs. Copyright ©
ISSN:1075-2617
DOI:10.1002/psc.886
出版商:John Wiley&Sons, Ltd.
年代:2007
数据来源: WILEY
|
8. |
Three‐dimensional holograph vector of atomic interaction field (3D‐HoVAIF): a novel rotation–translation invariant 3D structure descriptor and its applications to peptides |
|
Journal of Peptide Science,
Volume 13,
Issue 8,
2007,
Page 549-566
Feifei Tian,
Peng Zhou,
Fenglin Lv,
Rong Song,
Zhiliang Li,
Preview
|
|
摘要:
AbstractQuantitative structure–activity relationship (QSAR) study, important in drug design, mainly involves two aspects, molecular structural characterization (MSC) and construction of a statistical model. MSC focuses on transforming molecular structural and property characteristics into a group of numerical codes, dedicated to minimizing information loss during this process. In this context, common atoms in organic compounds are classified according to their families in the periodic table, and hybridization states, and on the basis of these, three nonbonding interactions (i.e. electrostatic, van der Waals and hydrophobic) are calculated, ultimately resulting in a new rotation–translation invariant, 3D‐MSC, as a three‐dimensional holograph vector of atomic interaction field (3D‐HoVAIF). By applying 3D‐HoVAIF to QSAR studies on two classical peptides including 58 angiotensin‐converting enzyme (ACE) inhibitors and 48 bitter‐tasting dipeptides, we get two excellent genetic algorithm‐partial least squares (GA‐PLS) models, with statisticsr2,q2, root mean square error (RMSEE), and root mean square error of cross‐validation (RMSCV) of 0.857, 0.811, 0.376, and 0.432 for ACE inhibitors and 0.940, 0.892, 0.153 and 0.205 for bitter‐tasting dipeptides, respectively. By equally dividing the two datasets into training and test sets by D‐optimal, the 3D‐HoVAIF approach undergoes rigorous statistical validation. Furthermore, the superior performance of 3D‐HoVAIF is confirmed in comparison with two other peptide MSC approaches referring to z‐scale and ISA‐ECI. For 58 ACE inhibitors, the GA‐PLS model yields two principal components, with the following statistics:r2= 0.893,q2= 0.824, RMSEE = 0.349, RMSCV = 0.425,$q_{\rm {ext}}^{2} = 0.739$,$r_{\rm {ext}}^{2} = 0.784$,$r_{0, {\rm {ext}}}^{2} = 0.781$,$r_{0, ext}^{'2} = 0.779$,k= 0.962,k′ = 1.019, and RMSEP = 0.460; for 48 bitter‐tasting dipeptides, three principal components resulted, with the statistics as:r2= 0.950,q2= 0.893, RMSEE = 0.152, RMSCV = 0.222,$q_{ext}^{2} = 0.875$,$r_{ext}^{2} = 0.919$,$r_{0, ext}^{2} = 0.919$,$r_{0, ext}^{'2} = 0.919$,k= 1.018,k′ = 0.974, and RMSEP = 0.198. In addition, the relationship of ACE‐inhibiting activities with bitter‐tasting thresholds has been investigated by applying the above‐constructed models to predictions on 400 theoretically possible dipeptides. Through analysis, the ACE‐inhibiting activities are found to be prominently related to bitter‐tasting intensities. Thus, it is deemed to be difficult to find such dipeptides that simultaneously satisfy pharmacodynamic action (high ACE‐inhibiting activities) and comfortable tastes, suggesting that active components of dipeptides that are served as functional food to lower blood pressure are not very ideal. Copyright ©
ISSN:1075-2617
DOI:10.1002/psc.892
出版商:John Wiley&Sons, Ltd.
年代:2007
数据来源: WILEY
|
|