摘要:

AbstractGLP‐1 is an incretin peptide involved in the regulation of glucose metabolism and the glucose‐dependent stimulation of insulin secretion. Ex‐4 is a paralog of GLP‐1 that has comparable GLP‐1R potency but extended physiological action. GLP‐1 and Ex‐4 are helical peptides that share ∼50% sequence homology but differ at several residues, notably the second amino acid which controls susceptibility to DPP‐IV cleavage. This single amino acid difference yields divergent receptor potency when studied in the context of the two hormone sequences. Ex‐4 uniquely tolerates Gly2 through select amino acid differences in the middle region of the peptide that are absent in GLP‐1. We report that substitution of Ex‐4 amino acids Glu16, Leu21, and Glu24 to the GLP‐1 sequence enabled Gly2 tolerance. The coordination of the N‐terminus with these central residues shows an interaction of substantial importance not only to DPP‐IV stability but also to receptor activation. Extension of this observation to glucagon‐based co‐agonist peptides showed different structural requirements for effective communication between the N‐terminus and the mid‐section of these peptides in achieving high potency agonism at the GLP‐1 and GCGRs. Copyright © 2011 European

ISSN:1075-2617    

DOI:10.1002/psc.1385

出版商:John Wiley&Sons, Ltd.    

年代:2011

数据来源: WILEY

摘要:

AbstractId1 proteins, inhibitors of differentiation or DNA binding, act as dominant negative antagonists of the bHLH family of transcription factors, which play an important role in cellular development, proliferation, and differentiation. The mechanism of Id proteins is to antagonize bHLH proteins by forming high‐affinity heterodimers with other bHLH proteins, thereby preventing them from binding to DNA and inhibiting transcription of differentiation‐associated genes. Our goal is to study the SARs of a peptidic antagonist of Id1, peptide 3C, which exhibits high affinity for Id1 and inhibitory effect on the proliferation of cancer cells. A series of N‐terminal‐ and C‐terminal‐deleted analogs of peptide 3C were designed, synthesized, and characterized. Affinity of each peptide for Id1 or Id1‐HLH domain was determined by SPR‐based biosensor. The secondary structure of each peptide was studied by CD spectroscopy. Biological effect of each peptide in breast cancer cell (MCF‐7) was analyzed by the MTT cell viability assay. Results demonstrated that peptide 3C and peptide 3C‐CtD4 exhibited higher affinity for Id1‐HLH and the equilibrium dissociation constants (KD) were 3.16 and 2.77 µM, respectively. CD results indicated that the percentage of α‐helix (%) in the secondary structure of deleted peptides were different, ranging from 7.93 to 10.45%. Although MTT results showed that treatment of MCF‐7 with these peptides did not cause antiproliferative effects in cancer cells, SPR results demonstrated that the high‐affinity peptides 3C and 3C‐CtD4 are promising for further modifications to enhance their affinity for Id1‐HLH and antiproliferative effects in cancer cells and for the development of peptidic antagonists as anticancer agents. Copyright © 2011 European Peptid

ISSN:1075-2617    

DOI:10.1002/psc.1386

出版商:John Wiley&Sons, Ltd.    

年代:2011

数据来源: WILEY

摘要:

AbstractProtaetiamycine is an insect defensin, derived from the larvae of the beetleProtaetia brevitarsis. In our previous work, we designed 9‐mer peptide analogs of protaetiamycine, including 9Pbw2 (RLWLAIKRR‐NH2), 9Pbw3 (RLWLAIWRR‐NH2), and 9Pbw4 (RLWLAWKRR‐NH2). 9Pbw2 and 9Pbw4 showed high antimicrobial activity without cytotoxicity, while 9Pbw3 with higher hydrophobicity compared to 9Pbw2 and 9Pbw4 showed high cytotoxicity as well as high antimicrobial activity (Shinet al.,J. Pept. Sci.2009; 15: 559–568). In this study, we investigated the anti‐inflammatory activities of 9Pbw2, 9Pbw3, and 9Pbw4 by quantitation of NO production in LPS‐stimulated RAW264.7 cells. The results showed that only 9Pbw3 has strong inhibition of NO production, implying that Trp7as well as optimum level of hydrophobicity may play key roles in the anti‐inflammatory activity of 9Pbw3. In order to design potent anti‐inflammatory peptide with lower cytotoxicity as well as high stability from cleavage by protease compared to 9Pbw3, we synthesized 9Pbw3‐D, the all‐D‐amino acid analog of 9Pbw3. 9Pbw3‐Dshowed less cytotoxicity against RAW264.7 cells as well as considerably stronger inhibition of NO production and inflammation‐induced cytokine production in LPS‐stimulated RAW264.7 cells than 9Pbw3. 9Pbw3‐Dinhibited the gene expression of inflammatory‐induced cytokine significantly more than 9Pbw3 and showed high resistance to proteolytic digestion. Binding of 9Pbw3‐Dwith LPS caused higher enhancement of the FITC fluorescence as a result of its stronger interaction with LPS compared to that of 9Pbw3 and this result is in good agreement with their anti‐inflammatory activities. 9Pbw3‐Dwith higher anti‐inflammatory activity as well as lower cytotoxicity against mammalian cell compared to 9Pbw3 can be a potent noncytotoxic antibiotic candidates. Copyright © 2011 Europea

ISSN:1075-2617    

DOI:10.1002/psc.1387

出版商:John Wiley&Sons, Ltd.    

年代:2011

数据来源: WILEY

摘要:

AbstractDepsidomycin is a cyclic heptadepsi‐peptide isolated from the cultured broth ofStreptomyces lavendofoliaeMI951‐62F2. It exhibits significant antimicrobial and immunosuppressive activity. The total synthesis of a depsidomycin analogue in which 1,2‐piperazine‐3‐carboxylic acid was substituted with proline is described. After several trials using different strategies, the desired depsidomycin analogue was obtainedviastepwise synthesis starting by the amino acid ‘head’ and macrolactonization under Yamaguchi conditions. The cyclic depsipeptide was evaluated to have an minimum inhibitory concentration (MIC) of 4 µg/ml against H37RV and 16 µg/ml against MDR clinical strains of MTB (MDR‐MTB), while the linear precursor 8 also had MICs of 4 and 16 µg/ml for the susceptible and resistant strains, respectively. Copyright © 2011 European Peptide Society and J

ISSN:1075-2617    

DOI:10.1002/psc.1389

出版商:John Wiley&Sons, Ltd.    

年代:2011

数据来源: WILEY

摘要:

Abstractα,β‐Dehydroamino acid esters occur in nature. To investigate their conformational properties, a systematic theoretical analysis was performed on the model molecules Ac‐ΔXaa‐OMe [ΔXaa = ΔAla, (E)‐ΔAbu, (Z)‐ΔAbu, ΔVal] at the B3LYP/6‐311+ + G(d,p) level in the gas phase as well as in chloroform and water solutions with the self‐consistent reaction field‐polarisable continuum model method. The Fourier transform IR spectra in CCl4and CHCl3have been analysed as well as the analogous solid state conformations drawn from The Cambridge Structural Database. The ΔAla residue has a considerable tendency to adopt planar conformations C5 (ϕ, ψ ≈ − 180°, 180°) and β2 (ϕ, ψ ≈ − 180°, 0°), regardless of the environment. The ΔVal residue prefers the conformation β2 (ϕ, ψ ≈ − 120°, 0°) in a low polar environment, but the conformations α (ϕ, ψ ≈ − 55°, 35°) and β (ϕ, ψ ≈ − 55°, 145°) when the polarity increases. The ΔAbu residues reveal intermediate properties, but their conformational dispositions depend on configuration of the side chain of residue: (E)‐ΔAbu is similar to ΔAla, whereas (Z)‐ΔAbu to ΔVal. Results indicate that the low‐energy conformation β2 is the characteristic feature of dehydroamino acid esters. The studied molecules constitute conformational patterns for dehydroamino acid esters with various side chain substituents in either or bothZ

ISSN:1075-2617    

DOI:10.1002/psc.1390

出版商:John Wiley&Sons, Ltd.    

年代:2011

数据来源: WILEY

摘要:

AbstractThis article addresses the interactions of the synthetic antimicrobial peptide dermaseptin 01 (GLWSTIKQKGKEAAIAAA‐ KAAGQAALGAL‐NH2, DS 01) with phospholipid (PL) monolayers comprising (i) a lipid‐rich extract ofLeishmania amazonensis(LRE‐La), (ii) zwitterionic PL (dipalmitoylphosphatidylcholine, DPPC), and (iii) negatively charged PL (dipalmitoylphosphatidylglycerol, DPPG). The degree of interaction of DS 01 with the different biomembrane models was quantified from equilibrium and dynamic liquid‐air interface parameters. At low peptide concentrations, interactions between DS 01 and zwitterionic PL, as well as with the LRE‐La monolayers were very weak, whereas with negatively charged PLs the interactions were stronger. For peptide concentrations above 1 µg/ml, a considerable expansion of negatively charged monolayers occurred. In the case of DPPC, it was possible to return to the original lipid area in the condensed phase, suggesting that the peptide was expelled from the monolayer. However, in the case of DPPG, the average area per lipid molecule in the presence of DS 01 was higher than pure PLs even at high surface pressures, suggesting that at least part of DS 01 remained incorporated in the monolayer. For the LRE‐La monolayers, DS 01 also remained in the monolayer. This is the first report on the antiparasitic activity of AMPs using Langmuir monolayers of a natural lipid extract fromL. amazonensis.Copyright © 2011 European Peptide Society and John

ISSN:1075-2617    

DOI:10.1002/psc.1392

出版商:John Wiley&Sons, Ltd.    

年代:2011

数据来源: WILEY

摘要:

AbstractAttracted by the possibility to optimize time and yield of the synthesis of difficult peptide sequences by MW irradiation, we compared Fmoc/tBu MW‐assisted SPPS of 1–34N‐terminal fragment of parathyroid hormone‐related peptide (PTHrP) with its conventional SPPS carried out at RT. MWs were applied in both coupling and deprotection steps of SPPS protocol. During the stepwise elongation of the resin‐bound peptide, monitoring was conducted by performing MW‐assisted mini‐cleavages and analyzing them by UPLC‐ESI‐MS. Identification of some deletion sequences was helpful to recognize critical couplings and as such helped to guide the introduction of MW irradiations to these stages. Copyright © 2011 European Peptide Society and Jo

ISSN:1075-2617    

DOI:10.1002/psc.1395

出版商:John Wiley&Sons, Ltd.    

年代:2011

数据来源: WILEY