摘要:

AbstractA few solid phase and solution approaches of good repute were applied in parallel with the aim to provide optimized routes to Boc‐ and Fmoc‐tocinoic acid (3aand3c) and the corresponding Tyr(But) derivatives (3band3d). Boc‐tocinoic acid is known to couple with tripeptide amides to give substituted oxytocin precursors in high yields, requiring only Boc‐cleavage to furnish the corresponding hormone analogs with minimal loss of material. For comparison, two protected linear hexapeptides (2aand2b) were prepared on three polystyrene supports, two with acid‐labile handles and one a conventional chloromethylated resin, in yields of 62–82 and 58–76%, respectively. The intermediate2acould be converted to3awith physical data in agreement with those earlier reported. Similarly, the intermediate2bwas converted to3b. The highest yields for both2aand2bwere obtained with a 2‐chlorotrityl chloride resin, which in addition provided advantages with respect to overall speed and convenience. Additional syntheses of3cand3don this and of3con SASRIN resin, in conjunction with trityl instead of benzyl for side‐chain protection of cysteine, were also elaborated. Copyright © 2001 European Peptide Society and Jo

ISSN:1075-2617    

DOI:10.1002/psc.329

出版商:John Wiley&Sons, Ltd.    

年代:2001

数据来源: WILEY

摘要:

AbstractPrevious studies have indicated that proteolytic activation of pro‐hormones and pro‐proteins occurs most frequently at the level of basic amino acids arranged in doublets and that the dibasic sites are situated in or next toβ‐turns. Investigations utilizing synthetic peptides reproducing theN‐terminal processing domain of pro‐oxytocin‐neurophysin have suggested a close relationship between the secondary structure of the cleavage locus and enzyme recognition, the minimal recognized sequence being the ‐Pro‐Leu‐Gly‐Gly‐Lys‐Arg‐Ala‐Val‐Leu‐ segment of the native precursor. NMR investigations and energy minimization studies have demonstrated that this sequence is organized in two type‐IIβ‐turns involving the ‐Pro‐Leu‐Gly‐Gly‐ and ‐Lys‐Arg‐Ala‐Val‐ sequences. To further strengthen the above reported hypothesis and to study the role of turn subtypes, a new proline containing cyclic substrate of the processing enzyme, in which theN‐terminal side that comes before the Lys‐Arg pair is constrained to adopt a type‐IIβ‐turn, has been synthesized. The presence of a type‐IIβ‐turn structure in this cyclic peptide model has been demonstrated by a combined NMR, CD and FT‐IR absorption investigation. A preliminary study shows that PC1 is able to recognize and process our constrained subs

ISSN:1075-2617    

DOI:10.1002/psc.330

出版商:John Wiley&Sons, Ltd.    

年代:2001

数据来源: WILEY

摘要:

AbstractThe change of selectivity and the induction of antagonism by the insertion of 1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid (Tic) in the second position of several opioid peptides have led to the interpretation of Tyr‐Tic as a specific message domain forδ‐opioid antagonists and to the discovery of dipeptides with substantial opioid activity. Selectivity and activity increase enormously when Tyr is substituted by 2′,6′‐dimethyl tyrosine (Dmt), hinting that the side chain of Dmt fits a hydrophobic cavity of the receptor very tightly and precisely. We have investigated the specificity of this fit by systematic changes of the substituents on the aromatic ring of Tyr. Mono‐ and disubstitutions different from 2′,6′‐ invariably lead to catastrophic decreases of activity. The only substitution compatible with retention of substantial antagonism is 2′‐methyl. An analysis of the conformational properties of all analogues reveals that substitutions do not affect the global shape of the molecule significantly. Accordingly, it is possible to use the shape of the different side chains to map the hydrophobic cavity of the receptor. The resulting complementary image is funnel shaped. Copyright © 2001 European Peptide Soc

ISSN:1075-2617    

DOI:10.1002/psc.331

出版商:John Wiley&Sons, Ltd.    

年代:2001

数据来源: WILEY

摘要:

AbstractIn this paper we report the synthesis and a detailed NMR solution characterization of a new CCK8 analogue and its indium(III) complex, PK‐CCK8 and In‐PK‐CCK8. The new compounds contain a porphyrin moiety covalently bound through an amide bond to the side chain of a Lys residue introduced at theN‐terminus of CCK8. A molecular dynamics simulation, based on the NMR structure of the complex between CCK8 and theN‐terminal extracellular arm of the CCKAreceptor, is also reported. Both the NMR study and the molecular dynamics simulation indicate that the porphyrin–peptide conjugate might be able to bind to the CCKAreceptor model. The results of the molecular dynamics calculations show that the conformational features of the CCK8/CCKAreceptor model complex and of the PK‐CCK8/CCKAreceptor‐model complex are similar. This evidence supports the view that the introduction of the porphyrin‐Lys moiety does not influence the mode of ligand binding to the CCKAreceptor model. The NMR structure of PK‐CCK8 in DMSO consists of a well defined pseudo‐helicalN‐terminal region, while theC‐terminal region is flexible. Moreover, the absence of NOE contacts between the porphyrin and the peptide indicates that the macrocyclic ring is directed away from the peptide region involved in the binding with the receptor. Copyright © 2001 European Peptide Societ

ISSN:1075-2617    

DOI:10.1002/psc.337

出版商:John Wiley&Sons, Ltd.    

年代:2001

数据来源: WILEY

ISSN:1075-2617    

DOI:10.1002/psc.350

出版商:John Wiley&Sons, Ltd.    

年代:2001

数据来源: WILEY