摘要:

AbstractMalonate diesters containing a prochiral quaternary carbon have been successfully transformed into analogs of cysteine and serine. The chiral half‐esters are obtained in good yield, and enantioselectivity by selective hydrolysis using Pig‐Liver Esterase (PLE) as the catalyst. The resulting half‐ester intermediates are transformed into α2, 2‐, β2, 2‐, and β3, 3‐analogs of cysteine and serine. The methodology described here allows for the preparation of both enantiomers of the amino‐acid analogs by selective manipulation of the ester and acid functionalities. This divergent strategy allows a common synthetic strategy to be used to prepare a variety of unnatural amino‐acid classes from a common intermediate which should prove useful in the design of novel peptide libraries. Copyright © 2008 European Peptide Society and J

ISSN:1075-2617    

DOI:10.1002/psc.1052

出版商:John Wiley&Sons, Ltd.    

年代:2008

数据来源: WILEY

摘要:

AbstractFurther improvements related to the synthesis of peptides containing HmS are presented. Efficient synthetic protocols have been developed to synthesize “difficult” sequences containing aC‐terminal HmS residue, MeA–HmS or consecutive HmS. Preparative methods for orthogonalN‐ and/orC‐protected HmS(Ipr) derivatives are described. Their compatibility with standard solution or solid‐phase peptide chemistry protocols allows synthetic flexibility toward HmS‐containing peptides. In the synthesis of the sterically hindered dipeptides with theC‐terminal HmS(Ipr) residue, HATU proves the highest efficiency, as compared with the fluoride and PyBroP/DMAP coupling methods. The HATU method also outperforms the fluoride activation in the solid‐phase assembly of HmS homosequence. Specific protocols are described to overcome an undesired cyclization to diketopiperazines that occurs during the removal of Fmoc from dipeptides with theC‐terminal HmS(Ipr) or HmS residues, thus precluding theirC→Nelongation. The successful protocols involve: (i) the 2 + 1 condensation using mixed anhydride activation yielding the desired product with the highest optical integrity or (ii) use of the 2‐chlorotrityl resin as a solid support sterically suppressing the undesired cleavage due to diketopiperazine formation. The latter approach allows the mild conditions of peptide cleavage from solid support, preserving the isopropylidene protection and minimizing the undesiredN→O‐acyl migration that was observed under prolonged acid treatment used for cleaving the HmS peptide from the Wang resin. Copyright © 2008 European Peptide So

ISSN:1075-2617    

DOI:10.1002/psc.1054

出版商:John Wiley&Sons, Ltd.    

年代:2008

数据来源: WILEY

摘要:

AbstractThe nanoscale peptide YSGVCHTDLHAWHGDWPLPVK exhibits molecular chaperone activity and prevents protein aggregation under chemical and/or thermal stress. Here, His mutations of this peptide and their impact on chaperone activity were evaluated using theoretical techniques. Molecular dynamic (MD) simulations with simulated annealing (SA) of different mutant nanopeptides were employed to determine the contribution of the scaffolding His residues (H45, H49, H52), when mutated to Pro, on chaperone actionin vitro.Thein silicomutations of His residues to Pro (H45P, H49P, H52P) revealed loss of secondary ordered strand structure. However, a small part of the strand conformation was formed in the middle region of the native chaperone peptide. The His‐to‐Pro mutations resulted in decreased gyration radius (Rg) values and surface accessibility of the mutant peptides under the simulation times. The invariant dihedral angle (ϕ) values and the disrupting effects of the Pro residues indicated the coil conformation of mutant peptides. The failure of the chaperone‐like action in the Pro mutant peptides was consistent with their decreased effective accessible surfaces. The high variation of Φ value for His residues in native chaperone peptide leads to high flexibility, such as a minichaperone acting as a nanomachine at the molecular level. Our findings demonstrate that the peptide strand conformation motif with high flexibility at nanoscale is critical for chaperone activity. Copyright © 2008 European Peptide Society and John Wiley&S

ISSN:1075-2617    

DOI:10.1002/psc.1055

出版商:John Wiley&Sons, Ltd.    

年代:2008

数据来源: WILEY

摘要:

AbstractThe second extracellular loop (ECL2) of the Noc receptor has been proposed to be involved in ligand binding and selectivity. The interaction of Noc with a constrained cyclic synthetic peptide, mimicking the ECL2, has been studied using fluorescence and NMR spectroscopies. Selective binding was shown with a dissociation constant of ∼10 µM(observed with the constrained cyclic loop and not with the open chain), and residues involved in ligand binding and selectivity have been identified. This bimolecular complex is stabilized by (i) ionic interactions between the two Noc basic motives and the ECL2 acidic residues; (ii) hydrophobic contacts involving Noc FGGFN‐terminal sequence and an ECL2 tryptophane residue. Our data confirm that Noc receptor's ECL2 contributes actively to ligand binding and selectivity by providing the peptidic ligand with a low affinity‐binding site. Copyright © 2008 European Peptide Society and John Wiley&So

ISSN:1075-2617    

DOI:10.1002/psc.1057

出版商:John Wiley&Sons, Ltd.    

年代:2008

数据来源: WILEY

摘要:

AbstractThe αIIbβ3receptor, which is the most abundant receptor on the surface of platelets, can interact with a variety of adhesive proteins including fibrinogen, fibronectin and the von Willebrand factor. Fibrinogen binding on αIIbβ3is an event essential for platelet aggregation and thrombus formation. Mapping of the fibrinogen‐binding domains on αIIbsubunit suggested the sequence 313–332 as a possible binding site. This region was restricted to sequence αIIb313–320 (Y313MESRADR320) using synthetic octapeptides overlapping by six residues. The YMESRADR octapeptide inhibits ADP‐stimulated human platelets aggregation and binds to immobilized fibrinogen. In this study, we used the Ala scanning methodology within the sequence 313–320 aiming to evaluate the contribution of each amino acid in inhibiting platelet aggregation. It was found that the substitution of Y313, M314, E315or S316by A does not affect the activity of the parent octapeptide. The–RADR‐motif seems to be the most essential for the biological activity of the αIIb313–320 site. The conformational analysis of the YAESRADR, YMESAADR and YMESRAAR analogs by using NMR spectroscopy and distance geometry calculations revealed significant differences in their conformational states in DMSO‐d6. Copyright © 2008 European Peptide Society

ISSN:1075-2617    

DOI:10.1002/psc.1060

出版商:John Wiley&Sons, Ltd.    

年代:2008

数据来源: WILEY

摘要:

AbstractA novel strategy for a more efficient synthesis of difficult sequence‐containing peptides, theS‐acyl isopeptide method, was developed and successfully applied. A model pentapeptide Ac–Val–Val–Cys–Val–Val–NH2was synthesized via its water‐solubleS‐acyl isopeptide using anS‐acyl isodipeptide unit, Boc–Cys(Fmoc–Val)–OH. AnS‐acyl isopeptide possessing excellent water solubility could be readily and quantitatively converted to the native peptide via anSNintramolecular acyl migration reaction at pH 7.4. Thus, theS‐acyl isopeptide method provides a useful tool in peptide chemistry. Copyright © 2008 European Peptid

ISSN:1075-2617    

DOI:10.1002/psc.1053

出版商:John Wiley&Sons, Ltd.    

年代:2008

数据来源: WILEY

摘要:

AbstractThe inhibitors of DNA binding and cell differentiation Id1–4 are helix‐loop‐helix (HLH) proteins that negatively regulate DNA transcription by forming inactive dimers with ubiquitous and tissue‐specific bHLH proteins, including E47 and MyoD, respectively. Their highly conserved HLH domains are essential for heterodimerization, but can also self‐associate to highly stable, α‐helix‐rich structures at low micromolar peptide concentrations. Here, we show that the introduction of anO‐acyl isodipeptide unit involving the putativeN‐cap serine residue of theC‐terminal helix completely abrogates the propensity of the Id HLH analogue for any secondary and tertiary structure, resulting in a random coil, as shown by CD measurements in nonbuffered aqueous solutions. However, the HLH fold reappears as soon as anO→Nintramolecular acyl migration, which occurs spontaneously under physiological conditions, restores the nativeN‐cap serine residue. These results show that changes addressing theN‐terminus of theC‐terminal helix can dramatically influence the HLH structure, and suggest that local interactions at the junction between the loop and theC‐terminal helix might be crucial during the HLH folding process. Furthermore, the present study contributes to the evaluation of theO‐acyl isodipeptide unit as a powerful tool to introduce a conformational switch into peptides. Copyright © 2008 European Peptide

ISSN:1075-2617    

DOI:10.1002/psc.1059

出版商:John Wiley&Sons, Ltd.    

年代:2008

数据来源: WILEY

摘要:

AbstractPhage‐displayed peptides recognized by two monoclonal antibodies against glucitollysine were selected. The most prominent feature of the peptide panel was the presence of paired Cys in most of them (21/24 peptides). The availability of a wide variety of peptides having differently spaced paired Cys, as well as truly linear Cys‐free peptides, gave the opportunity to explore the role of disulfide bridges in phage selection. Some Cys‐containing peptides came from a Cys‐flanked cyclic 9‐mer library, but most of them (18/21) were derived from a totally random 12‐mer library, and hence the presence of Cys was dictated by the selector antibodies. Motifs shared by several peptides (potentially involved in binding) often contained or were flanked by Cys residues. Binding of all Cys‐containing phage‐displayed peptides was abolished/decreased after a reducing treatment. Screening a random peptide library (without invariant Cys residues) is powerful enough to clearly reveal the need, preferences, and diversity of Cys‐mediated structural constraints for recognition. Copyright © 2008 European Peptide Society and Jo

ISSN:1075-2617    

DOI:10.1002/psc.1061

出版商:John Wiley&Sons, Ltd.    

年代:2008

数据来源: WILEY