RESUMO
Daptomycin is a highly effective lipopeptide antibiotic against Gram-positive pathogens. The presence of (2S, 3R) 3-methyl glutamic acid (mGlu) in daptomycin has been found to be important to the antibacterial activity. However the role of (2S, 3R) mGlu is yet to be revealed. Herein, we reported the syntheses of three daptomycin analogues with (2S, 3R) mGlu substituted by (2S, 3R) methyl glutamine (mGln), dimethyl glutamic acid and (2S, 3R) ethyl glutamic acid (eGlu), respectively, and their antibacterial activities. The detailed synthesis of dimethyl glutamic acid was also reported.
Assuntos
Antibacterianos/química , Daptomicina/análogos & derivados , Ácido Glutâmico/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Daptomicina/síntese química , Daptomicina/farmacologia , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
An efficient method has been developed for the salicylaldehyde ester-mediated ligation of unprotected peptides at serine (Ser) or threonine (Thr) residues. The utility of this peptide ligation approach has been demonstrated through the convergent syntheses of two therapeutic peptides--ovine-corticoliberin and Forteo--and the human erythrocyte acylphosphatase protein (â¼11 kDa). The requisite peptide salicylaldehyde ester precursor is prepared in an epimerization-free manner via Fmoc-solid-phase peptide synthesis.
Assuntos
Hidrolases Anidrido Ácido/síntese química , Aldeídos/química , Hormônio Liberador da Corticotropina/síntese química , Peptídeos/química , Engenharia de Proteínas/métodos , Teriparatida/síntese química , Animais , Cromatografia Líquida de Alta Pressão , Humanos , Espectrometria de Massas , Estrutura Molecular , Serina/química , Ovinos , Treonina/química , AcilfosfataseRESUMO
Covering: 2000 to 2014Cyclic peptides are a class of abundant natural products, often exhibiting attractive biological activities. The challenges in the total synthesis of cyclic peptides lie in the preparation of unnatural amino acids if present and the peptide cyclization. Cyclization is an entropy-disfavoured process, with competition between intermolecular and intramolecular reactions. Biological methods can utilize the pre-organized conformation of the side chain unprotected peptide, which brings the reacting termini into proximity, while chemical synthesis requires protecting groups, often large-size and hydrophobic in nature. In this regard, performing peptide cyclization can be an arbitrary and trial-and-error practice. In this highlight, we discuss the application of chemoselective ligation-mediated peptide cyclization in the total synthesis of natural cyclic peptides.
Assuntos
Produtos Biológicos/química , Peptídeos Cíclicos/química , Serina/química , Treonina/química , Produtos Biológicos/síntese química , Produtos Biológicos/farmacologia , Técnicas de Química Sintética , Ciclização , Estrutura Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologiaRESUMO
Daptomycin, the first antibiotic of its class, provides a new structural motif for the development of new antibiotics. Recently, we have completed the total synthesis of daptomycin. The development of the successful synthetic strategy is described here, including the application of serine/threonine ligation mediated peptide cyclization to the daptomycin macrocyclization.
Assuntos
Antibacterianos/síntese química , Daptomicina/síntese química , Antibacterianos/química , Daptomicina/químicaRESUMO
A total synthesis of daptomycin, the first natural product antibiotic launched in a generation, was achieved. This convergent synthesis relies on an efficient macrocyclization via a serine ligation to assemble the 31-membered cyclic depsipeptide. The difficult esterification by the nonproteinogenic amino acid kynurenine was accomplished via the esterification of a threonine residue by a suitably protected Trp ester, followed by ozonolysis. This synthesis provides a foundation and framework to prepare varied analogues of daptomycin to establish its structure-activity profile.
Assuntos
Antibacterianos/síntese química , Daptomicina/síntese química , Serina/química , Aminoácidos/química , Ciclização , Indicadores e Reagentes , Cinurenina/química , Lactamas/síntese química , Lactamas/química , Ligantes , Ozônio/química , Relação Estrutura-Atividade , Treonina/químicaRESUMO
The preparation of Kyn-containing peptides is difficult, owing to the low reactivity of Kyn in the coupling reaction. In this report, Kyn-containing peptides were efficiently obtained via on-resin ozonolysis of the corresponding Trp-containing peptide. In addition, a Kyn-containing cyclic peptide, cyclomontanin B, has been synthesized by this strategy in the combination with serine/threonine ligation (STL)-mediated cyclization.
Assuntos
Cinurenina/química , Ozônio/química , Peptídeos Cíclicos/síntese química , Peptídeos/síntese química , Resinas Sintéticas/química , Triptofano/química , Ciclização , Conformação Molecular , Peptídeos/química , Peptídeos Cíclicos/químicaRESUMO
The 5-lysyl-hydroxylation has been found among protein post-translational modifications. In this report, we have devised a fluorescence turn-on probe which allows for selectively recognizing 5-hydroxylysine-containing peptides.
Assuntos
Corantes Fluorescentes/química , Hidroxilisina/química , Fragmentos de Peptídeos/química , Proteínas/química , Serina/química , Treonina/químicaRESUMO
Serine/Threonine ligation (STL) has emerged as an alternative tool for protein chemical synthesis, bioconjugations as well as macrocyclization of peptides of various sizes. Owning to the high abundance of Ser/Thr residues in natural peptides and proteins, STL is expected to find a wide range of applications in chemical biology research. Herein, we have fully investigated the compatibility of the STL strategy for X-Ser/Thr ligation sites, where X is any of the 20 naturally occurring amino acids. Our studies have shown that 17 amino acids are suitable for ligation, while Asp, Glu, and Lys are not compatible. Among the working 17 C-terminal amino acids, the retarded reaction resulted from the bulky ß-branched amino acid (Thr, Val, and Ile) is not seen under the current ligation condition. We have also investigated the chemoselectivity involving the amino group of the internal lysine which may compete with the N-terminal Ser/Thr for reaction with the C-terminal salicylaldehyde (SAL) ester aldehyde group. The result suggested that the free internal amino group does not adversely slow down the ligation rate.
RESUMO
Syntheses of MUC1 glycopeptides (40-mer and 80-mer) are described. The convergent synthesis was achieved by native serine ligation using side-chain unprotected glycopeptide segments.
Assuntos
Glicopeptídeos/química , Mucina-1/química , Serina/química , Aldeídos/química , Cromatografia Líquida de Alta PressãoRESUMO
A serine/threonine-based chemoselective ligation method is described. It uses an O-salicylaldehyde ester at the C-terminus, reacting with N-terminal serine or threonine to realize peptide ligations. The utility of the O-salicylaldehyde ester enables the rapid coupling reaction and the production of an N,O-benzylidene acetal intermediate, which is readily converted into natural peptidic linkages (Xaa-Ser/Thr) at the ligation site.