摘要:

AbstractWe report 104 analogues of the potent antiovulatory antagonist of LHRH, N‐Ac‐D‐Nal‐D‐Cpa‐D‐Pal‐Ser‐Lys(Nic)‐D‐Lys(Nic)‐Leu‐Ilys‐Pro‐D‐Ala‐NH2, Antide. We replaced the Nic group in Antide with other acyl substituents to modulate size, hydrophilicity or basicity of the molecule, we also replaced th Lys residues with shorter basic amino acids, and made cyclic 5/6 analogues as well as position 5 or 6 dimers. We substituted Ilys8with other alkyl groups and acyl derivatives. When injected in 0.1% DMSO in water in a typical antiovulatory (AO) assay, Antide gives six rats ovulating out of eight (6/8) at 2 μg, 4/8 at 4 μg, and the histamine release assay (HRA), ED50is>300 μg/ml; [Lys(N‐Isobutyl)8]Antide gave 2/8 at 2 μg/rat; [Lys (8‐Qis)5]Antide gave 1/8 at 1 μg, and 0/8 at 2 μg, and in the HRA ED50, 22 μg/ml; [D‐Lys(8‐Qis)6]Antide gave 4/8 at 1 μg and 0/8 at 2 μg, and in the HRA, ED50was 27 μg/ml; [Lys(8‐Qic)8] gave 5/8 at 1 μg, 1/8 at 2 μg/ [Lys(2‐Pyc)5]Antide gave 5/8 at 1 μg and 0/8 at 2 μg, and in the HRA ED50was 116 μg/ml; [D‐Lys (2‐Pyc)6]Antide gave 3/8 at 1 μg, and in the HRA, ED50was 100 ‐>300 μg/ml; [Lys(2‐Pyc)5,D‐Lys(2‐Pyc)6]Antide gave 2/8 at 1 μg. The substitutions of the Nic groups of Antide at Lys5orD‐Lys6with 8‐Qis or with 2‐Pyc groups seem to give highly potent antiovulatory antagonists of LHRH and constitute significant new leads to gener

ISSN:1075-2617    

DOI:10.1002/psc.310010202

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe variable domain V3 in the outer glycoprotein gp 120 of HIV‐1 is a highly important region with respect to immune response during the course of viral infection. Neutralizing antibodies are produced against this domain; in addition, it has been shown to be a functionally active epitope for T helper and cytotoxic T cells. The high degree of amino acid variability in individual HIV‐isolates, however, limits the use of the V3‐domain in approaches to vaccine development. In order to characterize the residues important for antibody interaction and binding to MHC class I proteins, we constructed a consensus sequence of the V3‐domain with broad reactivity [1] and used synthetic peptides derived from this consensus with individual residues altered to alanine. These peptides were used as antigens in ELISA tests to define the amino acids which are important for binding to human and rabbit/anti‐peptide immunoglobulins. In addition, we used these alanine‐derived peptides in interaction studies with human HLA‐A2.1 and mouse H‐2Ddby testing their capacity to stabilize the respective MHC class I protein complexes on the surface of mutant cell lines T2 and RMA‐S transfected withDdgene. The experimental tests allowed us to define individual residues involved in antibody and MHC‐protein interaction, respectively. In a further approach, we used those results to design interaction models with HLA‐A2.1 and H‐2Dd. Therefore, a structural model for H‐2Ddwas built that exhibits an overall similar conformation to the parental crystal structure of HLA‐A2.1. The resulting interaction models show V3‐peptide bound in an extended β‐conformation with a bulge in its centre for both H‐2Ddand HLA‐A2.1 complexes. The N‐ and C‐termini of V3 peptide reside in conserved pockets within both MHC‐proteins. Anchoring residues could be determined that are crucial for the binding of the respective MHC class I haplotype. The cross‐reactivity of V3‐peptide in enhancing the expression of two different MHC class I molecules (H‐2Ddand HLA‐A2.1) is shown to be based on similar peptide binding tha

ISSN:1075-2617    

DOI:10.1002/psc.310010203

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractN‐Urethane‐protectedN‐carboxyanhydrides (UNCAs) are very reactives. They have been successfully used in peptide synthesis, in both solution and solid phase. We have demonstrated that UNCAs are interesting starting materials for the synthesis of various amino acid derivatives. Chemoselective reduction of UNCAs with sodium borohydride led the correspondingN‐protected β amino alcohols. Reaction of UNCAs with Meldrum's acid, followed by cyclisation, yielded enantiomerially pure tetramic acid derivatives. Diastereoselective reduction of tetramic acid derivatives produced (4S,5S)‐N‐alkoxycarbonyl‐4‐hydroxy‐5‐alkylpyrrolidin‐2‐ones derived from amino acids, which after hydrolysis yielded statine and statine analogues. Tetramic acid derivatives could also be obtained by reaction of UNCAs with benzyl ethyl followed by hydrogenolytic deprotection and decarboxylation. UNCAs also reacted with phosphoranes to produce the ketophosphorane in excellent yields. Subsequent oxidation with oxone or with [bis(acetoxy)‐iodol]‐benzene produced vicinal tricarbonyl derivatives. These reactions usually proceeded s

ISSN:1075-2617    

DOI:10.1002/psc.310010204

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

Abstractγ‐secretase, the endoprotease which releases the C‐terminus of βA4 amyloid peptide, cleaves within the hydrophobic transmembrane domain of the amyloid precursor protein. In order to obtain a substrate for γ‐secretase, a dodecapeptide which spans the cleavage site was synthesized, labelled with 125‐iodine and conjugated to an agarose gel. A radiometric solid‐phase assay was developed using this immobilized substrate. Peptide products were separated by reverse‐phase HPLC and TLC to allow characterization of the cl

ISSN:1075-2617    

DOI:10.1002/psc.310010205

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractPeptides derived from the bee‐venom melittin were fitted with the haptenic group dinitrocarboxyphenyl(Dncp) and tested in out‐bred guinea pigs for immunogenicity by measuring the IgG anti‐Dncp antibody response by ELISA. Dncp‐conjugates comprising virtually the entire melittin proved to be strong immunogens producing antibody responses comparable to those of proteins. Weak responses were obtained with considerably shortened seqences. Conjugates with N‐terminal Dncp gave markedly reduced antibody responses compared to peptides with C‐terminal Dncp. An N‐terminal biotinyl substituent abolished the immune response whereas N‐terminal lauryl and caprylyl had little effect. Insertion of L‐proline into a hexadecapeptide conjugate abolishing the possibility of helix formation gave an immunogen to which individual animals clearly responded on a low level. Oligomerisation, but not the cytolytic activity of melittin peptides, may contribute to the immunoge

ISSN:1075-2617    

DOI:10.1002/psc.310010206

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

ISSN:1075-2617    

DOI:10.1002/psc.310010201

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY