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1.
J Pept Res ; 66(6): 333-47, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16316449

RESUMO

A homologous series of nonapeptides and their acetylated versions were successfully prepared using solid-phase synthetic techniques. Each nonapeptide was rich in alpha,alpha-dialkylated amino acids [one 4-aminopiperidine-4-carboxylic acid (Api) and six alpha-aminoisobutyric acid (Aib) residues] and also included lysines or lysine analogs (two residues). The incorporation of the protected dipeptide 9-fluorenylmethyloxycarbonyl (Fmoc)-Aib-Aib-OH improved the purity and overall yields of these de novo designed peptides. The helix preference of each nonapeptide was investigated in six different solvent environments, and each peptide's antimicrobial activity and cytotoxicity were studied. The 3(10)-helical, amphipathic design of these peptides was born out most prominently in the N-terminally acetylated peptides. Most of the peptides exhibited modest activity against Escherichia coli and no activity against Staphylococcus aureus. The nonacetylated peptides (concentrations < or =100 microM) and the acetylated peptides (concentrations < or = 200 microM) did not exhibit any significant cytotoxicity with normal (nonactivated) murine macrophages.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Peptídeos/química , Peptídeos/farmacologia , Animais , Antibacterianos/síntese química , Células Cultivadas , Dicroísmo Circular , Relação Dose-Resposta a Droga , Escherichia coli/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Fragmentos de Peptídeos , Peptídeos/síntese química , Proinsulina , Staphylococcus aureus/efeitos dos fármacos
4.
J Med Chem ; 39(16): 3107-13, 1996 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-8759631

RESUMO

De novo antimicrobial peptides with the sequences: (KLAKKLA)n, (KLAKLAK)n (where n = 1,2,3), (KALKALK)3, (KLGKKLG)n, and (KAAKKAA)n (where n = 2,3), were prepared as the C-terminus amides. These peptides were designed to be perfectly amphipathic in helical conformations. Peptide antibacterial activity was tested against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. Peptide cytotoxicity was tested against human erythrocytes and 3T3 mouse fibroblasts. The 3T3 cell testing was a much more sensitive test of cytotoxicity. The peptides were much less lytic toward human erythrocytes than 3T3 cells. Peptide secondary structure in aqueous solution, sodium dodecylsulfate micelles, and phospholipid vesicles was estimated using circular dichroism spectroscopy. The leucine/alanine-containing 21-mers were bacteriostatic at 3-8 microM and cytotoxic to 3T3 cells at about 10 microM concentrations. The leucine/alanine- or leucine/glycine-containing 14-mers and the leucine/glycine 21-mer were bacteriostatic at 6-22 microM but had much lower cytotoxicity toward 3T3 cells and higher selectivities than the natural antimicrobial peptides magainin 2 amide and cecropin B amide. The 7-mer peptides are devoid of biological activity and of secondary structure in membrane mimetic environments. The 14-mer peptides and the glycine-containing 21-mer show modest levels of helicity in model membranes. The leucine/alanine-containing 21-mer peptides have substantial helicity in model membranes. The propensity to alpha-helical conformation of the peptides in amphipathic media is proportional to their 3T3 cell cytotoxicity.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Peptídeos/farmacologia , Células 3T3 , Sequência de Aminoácidos , Animais , Antibacterianos/química , Dicroísmo Circular , Eritrócitos/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Humanos , Lipossomos , Camundongos , Micelas , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Peptídeos/química , Estrutura Secundária de Proteína , Pseudomonas aeruginosa/efeitos dos fármacos , Dodecilsulfato de Sódio , Staphylococcus/efeitos dos fármacos
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