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1.
Eur J Med Chem ; 221: 113488, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33991963

RESUMO

Naturally occurring cyclic antimicrobial peptides (AMPs) such as tyrocidine A (Tyrc A) and gramicidin S (GS) are appealing targets for the development of novel antibiotics. However, their therapeutic potentials are limited by undesired hemolytic activity and relatively poor activity against Gram-negative bacteria. Inspired by polycationic lipopeptide polymyxin B (PMB), the so called 'last-resort' antibiotic for the treatment of infections caused by multidrug-resistant Gram-negative bacteria, we synthesized and biologically evaluated a series of polycationic analogues derived from Tyrc A. We were able to obtain peptide 8 that possesses 5 positive charges exhibiting potent activities against both Gram-negative and Gram-positive bacteria along with totally diminished hemolytic activity. Intriguingly, antibacterial mechanism studies revealed that, rather than the 'pore forming' model that possessed by Tyrc A, peptide 8 likely diffuses membrane in a 'detergent-like' manner. Furthermore, when treating mice with peritonitis-sepsis, peptide 8 showed excellent antibacterial and anti-inflammatory activities in vivo.


Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Polimixina B/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Tirocidina/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Linhagem Celular , Relação Dose-Resposta a Droga , Farmacorresistência Bacteriana/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Polimixina B/química , Relação Estrutura-Atividade , Tirocidina/síntese química , Tirocidina/química
2.
J Am Chem Soc ; 143(7): 2736-2740, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33570948

RESUMO

Nonribosomal peptides (NRPs) are a therapeutically important class of secondary metabolites that are produced by modular synthetases in assembly-line fashion. We previously showed that a single Trp-to-Ser mutation in the initial Phe-loading adenylation domain of tyrocidine synthetase completely switches the specificity toward clickable analogues. Here we report that this minimally invasive strategy enables efficient functionalization of the bioactive NRP on the pathway level. In a reconstituted tyrocidine synthetase, the W227S point mutation permitted selective incorporation of Phe analogues with alkyne, halogen, and benzoyl substituents by the initiation module. The respective W2742S mutation in module 4 similarly permits efficient incorporation of these functionalized substrate analogues at position 4, expanding this strategy to elongation modules. Efficient incorporation of an alkyne handle at position 1 or 4 of tyrocidine A allowed site-selective one-step fluorescent labeling of the corresponding tyrocidine analogues by Cu(I)-catalyzed alkyne-azide cycloaddition. By combining synthetic biology with bioorthogonal chemistry, this approach holds great potential for NRP isolation and molecular target elucidation as well as combinatorial optimization of NRP therapeutics.


Assuntos
Peptídeos/metabolismo , Alcinos/química , Azidas/química , Catálise , Cobre/química , Reação de Cicloadição , Corantes Fluorescentes/química , Mutagênese Sítio-Dirigida , Biossíntese de Peptídeos Independentes de Ácido Nucleico , Peptídeo Sintases/genética , Peptídeo Sintases/metabolismo , Peptídeos/química , Tirocidina/análogos & derivados , Tirocidina/síntese química
3.
Nat Prod Rep ; 33(2): 127-35, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26175103

RESUMO

Appreciation that some cyclic peptide antibiotics such as gramicidin S and tyrocidine were nonribosomally synthesized has been known for 50 years. The past two decades of research including advances in bacterial genetics, genomics, protein biochemistry and mass spectrometry have codified the principles of assembly line enzymology for hundreds of nonribosomal peptides and in parallel for thousands of polyketides. The advances in understanding the strategies used for chain initiation, elongation and termination from these assembly lines have revitalized natural product biosynthetic communities.


Assuntos
Bactérias/enzimologia , Produtos Biológicos/síntese química , Gramicidina/síntese química , Peptídeo Sintases/metabolismo , Peptídeos Cíclicos/síntese química , Policetídeos/química , Tirocidina/síntese química , Bactérias/metabolismo , Produtos Biológicos/química , Gramicidina/química , Estrutura Molecular , Peptídeos Cíclicos/química , Tirocidina/química
4.
J Pept Sci ; 21(7): 586-92, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25900908

RESUMO

Glycosylation can have a multifaceted impact on the properties and functions of peptides and plays a critical role in interacting with or binding to the target molecules. Herein, based on the previously reported method for macrocyclic glycopeptide synthesis, two series of tyrocidine A glycosylated derivatives (1a-f and 2a-f) were synthesized and evaluated for their antibacterial activities to further study the structure and activity relationships (SAR). Biological studies showed that the synthetic glycosylated derivatives had good antibacterial activities towards methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. SAR studies based on various glycans and linkages were used to enhance the biochemical profile, resulting in the identification of several potent antibiotics, such as 1f, with a great improved therapeutic index than tyrocidine A.


Assuntos
Antibacterianos/síntese química , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Tirocidina/análogos & derivados , Enterococos Resistentes à Vancomicina/efeitos dos fármacos , Sequência de Aminoácidos , Antibacterianos/farmacologia , Glicosilação , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tirocidina/síntese química , Tirocidina/farmacologia , Enterococos Resistentes à Vancomicina/crescimento & desenvolvimento
5.
J Med Chem ; 52(7): 2052-9, 2009 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-19281223

RESUMO

An efficient and practical method for macrocyclic glycopeptide synthesis was developed and utilized to synthesize tyrocidine A and its glycosylated derivatives. The method is based on solid-phase peptide synthesis using 2-chlorotrityl resin as the solid-phase support and glycosyl amino acids as building blocks. After glycopeptides with fully protected glycans and side chains were released from the acid-labile resin, their C- and N-termini were intramolecularly coupled in solution to afford cyclic glycopeptides in quantitative yields. This synthetic method should be generally applicable to various macrocyclic glycopeptides. Biological studies of the synthetic tyrocidine A derivatives showed that linking glycans directly to the Asn residue of tyrocidine A diminished its antibacterial activity, but linking glycans to Asn via a simple spacer did not. These results revealed the important impact of glycans on the activities, and probably the structures, of glycopeptide antibiotics.


Assuntos
Antibacterianos/síntese química , Glicopeptídeos/síntese química , Peptídeos Cíclicos/síntese química , Tirocidina/análogos & derivados , Tirocidina/síntese química , Antibacterianos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Glicopeptídeos/farmacologia , Glicosilação , Testes de Sensibilidade Microbiana , Peptídeos Cíclicos/farmacologia , Relação Estrutura-Atividade , Tirocidina/farmacologia
6.
J Am Chem Soc ; 128(39): 13000-9, 2006 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-17002397

RESUMO

Cyclic peptides provide attractive lead compounds for drug discovery and excellent molecular probes in biomedical research. Large combinatorial libraries of cyclic peptides can now be routinely synthesized by the split-and-pool method and screened against biological targets. However, post-screening sequence determination of hit peptides has been problematic. In this report, a high-throughput method for the sequence determination of cyclic peptide library members has been developed. TentaGel microbeads (90 mum) were spatially segregated into outer and inner layers; cyclic peptides were displayed on the bead surface, whereas the inner core of each bead contained the corresponding linear peptide as the encoding sequence. After screening of the cyclic peptide library against a macromolecular target, the identity of hit peptides was determined by sequencing the linear encoding peptides inside the bead using a partial Edman degradation/mass spectrometry method. On-bead screening of an octapeptide library (theoretical diversity of 160 000) identified cyclic peptides that bind to streptavidin. A 400-member library of tyrocidine A analogues was synthesized on TentaGel macrobeads and solution-phase screening of the library directly against bacterial cells identified a tyrocidine analogue of improved antibacterial activity. Our results demonstrate that the new method for cyclic peptide sequence determination is reliable, operationally simple, rapid, and inexpensive and should greatly expand the utility of cyclic peptides in biomedical research.


Assuntos
Peptídeos Cíclicos/análise , Análise de Sequência de Proteína/métodos , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Técnicas de Química Combinatória/métodos , Oligopeptídeos/análise , Oligopeptídeos/química , Biblioteca de Peptídeos , Peptídeos Cíclicos/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Estreptavidina/química , Tirocidina/síntese química , Tirocidina/química , Tirocidina/farmacologia
7.
J Med Chem ; 46(23): 4830-3, 2003 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-14584933

RESUMO

Using an alanine-scanning method, we have found that the antibacterial and hemolytic activities of the amphipathic cyclic decapeptide antibiotic tyrocidine A depend on different structural components. Single substitution of glutamine-6 of the natural product with a cationic amino acid results in a therapeutic index enhancement of up to 140-fold. Successful dissociation of the two intimately associated properties should enable discovery of novel analogues with both high bacterial selectivity and antibacterial potency to counter microbial resistance.


Assuntos
Antibacterianos/síntese química , Hemólise , Peptídeos Cíclicos/síntese química , Tirocidina/síntese química , Substituição de Aminoácidos , Antibacterianos/química , Antibacterianos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Farmacorresistência Bacteriana , Humanos , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Estrutura Secundária de Proteína , Espectrometria de Massas de Bombardeamento Rápido de Átomos , Relação Estrutura-Atividade , Tirocidina/química , Tirocidina/farmacologia
9.
Org Lett ; 4(17): 2893-5, 2002 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-12182582

RESUMO

[reaction: see text] Head-to-tail cyclization of peptides is a multistep process involving tedious C-terminal activation and side chain protection. Here we report a facile, quantitative cyclization method in aqueous ammonia solution for the total syntheses of the cyclic decapeptide antibiotic Tyrocidine A and its analogues from their fully deprotected linear thioester precursors on a solid support. This novel aqueous method is conformation-dependent and may be applicable to syntheses of other natural cyclic peptides.


Assuntos
Antibacterianos/síntese química , Tirocidina/síntese química , Ciclização , Peptídeos Cíclicos/síntese química , Soluções , Compostos de Sulfidrila/química
10.
Nature ; 418(6898): 658-61, 2002 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-12167866

RESUMO

Molecules in nature are often brought to a bioactive conformation by ring formation (macrocyclization). A recurrent theme in the enzymatic synthesis of macrocyclic compounds by non-ribosomal and polyketide synthetases is the tethering of activated linear intermediates through thioester linkages to carrier proteins, in a natural analogy to solid-phase synthesis. A terminal thioesterase domain of the synthetase catalyses release from the tether and cyclization. Here we show that an isolated thioesterase can catalyse the cyclization of linear peptides immobilized on a solid-phase support modified with a biomimetic linker, offering the possibility of merging natural-product biosynthesis with combinatorial solid-phase chemistry. Starting from the cyclic decapeptide antibiotic tyrocidine A, this chemoenzymatic approach allows us to diversify the linear peptide both to probe the enzymology of the macrocyclizing enzyme, TycC thioesterase, and to create a library of cyclic peptide antibiotic products. We have used this method to reveal natural-product analogues of potential therapeutic utility; these compounds have an increased preference for bacterial over eukaryotic membranes and an improved spectrum of activity against some common bacterial pathogens.


Assuntos
Antibacterianos/biossíntese , Antibacterianos/síntese química , Peptídeos Cíclicos/biossíntese , Peptídeos Cíclicos/síntese química , Sequência de Aminoácidos , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Produtos Biológicos/biossíntese , Produtos Biológicos/síntese química , Produtos Biológicos/farmacologia , Catálise , Ciclização , Eritrócitos/efeitos dos fármacos , Humanos , Hidrólise , Testes de Sensibilidade Microbiana , Mimetismo Molecular , Dados de Sequência Molecular , Peptídeos Cíclicos/farmacologia , Especificidade por Substrato , Tioléster Hidrolases/metabolismo , Tirocidina/análogos & derivados , Tirocidina/biossíntese , Tirocidina/síntese química , Tirocidina/farmacologia
11.
Int J Pept Protein Res ; 18(2): 127-34, 1981 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-6273346

RESUMO

Tyrocidine A (TA) is an antibiotic cyclic decapeptide with the sequence of cyclo (-L-Val1-L-Orn2-L-Leu3-D-Phe4-L-Pro5-L-Phe6-D-Phe7-L-Asn8-L-Gln9-L-Tyr10-). Gramicidin S (GS) regarded as a homolog of TA is also a cyclic decapeptide with the sequence of cyclo (-L-Val1-L-Orn2-L-Leu3-D-Phe4-L-Pro5-L-Val5-L-Orn7-L-Leu8-D-Phe9-L-Pro10-). GS shows higher antibacterial activity, whereas TA exhibits inhibitory activity on the biosynthesis of RNA. Two analogs of TA, [L-Val6]-TA (12a) and [L-Orn7]-TA (12b), were synthesized by the conventional method in order to study the interrelationships between the two related antibiotics TA and GS. Antibacterial activities of 12a and TA are nearly the same, but the activity of 12b is significantly lower. The optical rotatory dispersion spectra of 12a, 12b, and TA showed a trough at 233 nm region; the troughs of 12a and TA are nearly the same in depth, but the trough of 12b is shallower. Relationships between structure and activity of 12a and 12b compared with TA and GS were discussed.


Assuntos
Tirocidina/síntese química , Tirotricina/síntese química , Sequência de Aminoácidos , Bacillus subtilis/efeitos dos fármacos , Métodos , Dispersão Óptica Rotatória , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
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