Molecular construction of HIV-gp120 discontinuous epitope mimics by assembly of cyclic peptides on an orthogonal alkyne functionalized TAC-scaffold

Mimics of discontinuous epitopes of for example bacterial or viral proteins may have considerable potential for the development of synthetic vaccines, especially if conserved epitopes can be mimicked. However, due to the structural complexity and size of discontinuous epitopes molecular construction of these mimics remains challeging. We present here a convergent route for the assembly of discontinuous epitope mimics by successive azide alkyne cycloaddition on an orthogonal alkyne functionalized scaffold. Here the synthesis of mimics of the HIV gp120 discontinuous epitope that interacts with the CD4 receptor is described. The resulting protein mimics are capable of inhibition of the gp120–CD4 interaction. The route is convergent, robust and should be applicable to other discontinuous epitopes

Collagen degradation and neutrophilic infiltration: a vicious circle in inflammatory bowel disease

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Peptide transformation leading to peptide-peptidosulfonamide hybrids and oligo peptidosulfonamides

The sulfonamide moiety was introduced as a potential transition state isostere of the hydrolysis of the amide bond. Subsequently, the increased acidity of a sulfonamide N-H as compared to a regular amide N-H was explored in the development of peptidosulfonamide synthetic receptor molecules for binding and catalysis. The required building blocks for these compounds were accessible via an efficient synthesis, which also enabled the synthesis of oligopeptidosulfonamides as well as peptidosulfonamide-betapeptide hybrids. The structural consequences of the introduction of the peptidosulfonamide residues were studied and were further explored by the synthesis of cyclic peptidosulfonamides e.g. by ring-closing metathesis

Approaches to the synthesis of ureapeptoid peptidomimetics

Ureapeptoid peptidomimetics can be composed from Boc-protected N-substituted ethylenediamines. The best approach is to synthesize these from chloroacetonitrile followed by conversion to the corresponding crystalline p-nitrophenyl carbamates in order to prepare the ureapeptoids

A combinatorial approach toward smart libraries of discontinuous epitopes of HIV gp120 on a TAC synthetic scaffold

We describe rapid and convenient access to smart libraries of protein surface discontinuous epitope mimics. Up to three different cyclic peptides, representing discontinuous epitopes in HIV-gp120, were conjugated to a triazacyclophane scaffold molecule via CuAAC. In this way protein mimics for use as synthetic vaccines and beyond will become available

Synthesis of cyclic (α2β)-tripeptides as potential peptide turn mimetics

The solid-supported synthesis followed by cyclization in solution of cyclic (α2β)-tripeptides, potential peptide β-turn mimetics, is described. The cyclization takes advantage of facilitating the rotation between trans- and cis-rotamers of two amide bonds. The method is amenable to combinatorial approaches as is illustrated by the synthesis of a small array of cyclic (α2β)-tripeptides

Combinatorial chemistry of hydantoins

Access to combinatorial chemistry of hydantoins is provided by convenient and versatile methods for the solid phase synthesis of libraries of 3,5-, 1,3- and 1,3,5-substituted hydantoins. The preparation of trisubstituted hydantoins features a Mitsunobu reaction for introduction of the substituent on N-1

A convenient solid phase synthesis of S-palmitoyl transmembrane peptides

S-Palmitoylated peptides are important tools as models for integral membrane proteins to study peptide–lipid interactions. Herein, we report a convenient solid phase synthesis of S-palmitoyl transmembrane peptides. The highly acid labile S-(4-methoxytrityl) group is preferred over the S-(tert-butylsulfanyl) group for protection of the cysteine side chain since the latter gives rise to quantitative desulfurization during on-resin deprotection. The resulting free thiol function is modified with palmitic acid via a carbodiimide-mediated coupling and the title compounds are obtained in good yields and purity

Synthesis of cyclic peptidosulfonamides as scaffolds for MC4 pharmacophoric groups

The synthesis of potential β-turn mimetics based on cyclic sulfonamide peptoid/peptoid hybrids is described. These are readily synthesized using a solid phase protocol followed by cyclization in solution, and their suitability to combinatorial approaches is illustrated by the synthesis of a small but diversely functionalized library

A general approach for the non-stop solid phase synthesis of TAC-scaffolded loops towards protein mimics containing discontinuous epitopes

In this Communication, the access to three different peptide loops attached to a small triazacyclophane (TAC) scaffold molecule for the mimicry of discontinuous epitopes present in, for example, antibodies is described for the first time