RESUMO
To create a broad-spectrum peptide biocide, we synthesized 45 analogs of antimicrobial peptide indolicidin (H-Ile-Leu-Pro-Trp-Lys-Trp-Pro-Trp-Trp-Pro-Trp-Arg-Arg-NH2). Among them the peptides H-Ile-Leu-Pro-(2-Me)Phe-Lys-(2-Me)Phe-Pro-(2-Me)Phe-(2-Me)Phe-Pro-(2-Me)Phe-Arg-Arg-NH2 and HN2-(CH2)10-Ile-Leu-Pro-D-Phe-Lys-D-Phe-Pro-D-Phe-D-Phe-Pro-D-Phe-Arg-Arg-NH2 have the broadest spectrum of antimicrobial activity and the lowest hemolytic activity. They are active against all 11 tested strains of Gram-positive bacteria, Gram-negative bacteria and fungi with MIC50 from 0.9 to 6.1⯵g/ml (0.5 to 3.2⯵M), being up to 3 times more active than indolicidin, and are at least 1.8 times less hemolytically active than indolicidin (reached the detection limit). These peptides are patented and could be used for further drug development as antimicrobials.
Assuntos
Anti-Infecciosos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Peptídeos/síntese química , Sequência de Aminoácidos , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Peptídeos Catiônicos Antimicrobianos/síntese química , Peptídeos Catiônicos Antimicrobianos/química , Desenho de Fármacos , Hemólise/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Leveduras/efeitos dos fármacosRESUMO
Natural peptides with antimicrobial activity are extremely diverse, and peptide synthesis technologies make it possible to significantly improve their properties for specific tasks. Here, we investigate the biological properties of the natural peptide indolicidin and the indolicidin-derived novel synthetic peptide In-58. In-58 was generated by replacing all tryptophan residues on phenylalanine in D-configuration; the α-amino group in the main chain also was modified by unsaturated fatty acid. Compared with indolicidin, In-58 is more bactericidal, more resistant to proteinase K, and less toxic to mammalian cells. Using molecular physics approaches, we characterized the action of In-58 on bacterial cells at the cellular level. Also, we have found that studied peptides damage bacterial membranes. Using the Escherichia coli luminescent biosensor strain MG1655 (pcolD'::lux), we investigated the action of indolicidin and In-58 at the subcellular level. At subinhibitory concentrations, indolicidin and In-58 induced an SOS response. Our data suggest that indolicidin damages the DNA, but bacterial membrane perturbation is its principal mode of action. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.
Assuntos
Anti-Infecciosos/síntese química , Peptídeos Catiônicos Antimicrobianos/síntese química , Bactérias/efeitos dos fármacos , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Bactérias/genética , Bactérias/metabolismo , Membrana Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Modelos Moleculares , Resposta SOS em Genética/efeitos dos fármacosRESUMO
Patients with heart connective tissue dysplasia (HCTD) are known to be subject to infectious and inflammatory diseases due to peculiarities of their immune system. We studied 181 patients with HCTD depending on thyroid hormone levels and vegetative dysfunction. HCTD was shown to be associated with a significant decrease of IgM levels and increase of circulating immune complexes. The IgG level in patients with mitral valve prolapse (MVP), anomalous chord localization, and combination of MPV and tricuspid valve prolapse was significantly higher than in the absence of HCTD. Patients with and without HCTD showed the dependence of IgA levels on TSH concentration. In those with combined MPV the intensity of chemiluminescence was related to the T4 level. The dependence of IgM levels on he presence ofvegetative dysfunction was documented in patients with MVP.
Assuntos
Doenças do Tecido Conjuntivo/fisiopatologia , Cardiopatias/fisiopatologia , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Doenças do Tecido Conjuntivo/imunologia , Feminino , Cardiopatias/imunologia , Humanos , Imunoglobulina A/sangue , Medições Luminescentes , Masculino , Tireotropina/sangue , Tiroxina/sangue , Adulto JovemRESUMO
We studied the effect of vasopressin analogue desglycinamide-arginine-vasopressin on changes in platelet hemostasis produced by intragastric administration of Ticlid or clopidogrel (inhibitors of ADP-induced platelet aggregation). Intranasal administration of the peptide under conditions of hemorrhagic diathesis produced a hemostatic effect and normalized some parameters of blood coagulation.
Assuntos
Difosfato de Adenosina/metabolismo , Arginina Vasopressina/análogos & derivados , Agregação Plaquetária/efeitos dos fármacos , Vasopressinas/química , Animais , Arginina Vasopressina/farmacologia , Plaquetas/efeitos dos fármacos , Clopidogrel , Hemostasia/efeitos dos fármacos , Hemostáticos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Testes de Função Plaquetária , Ratos , Ticlopidina/análogos & derivados , Ticlopidina/farmacologiaRESUMO
The antibacterial peptide indolicidin and a number of its analogues were obtained by solid phase synthesis. An optimized method of the synthesis using the Boc strategy was suggested. It was shown that the therapeutic index of indolicidin analogues increased with a decrease in the total positive charge of the molecule and its amphipathicity; i.e., the hemolytic activity of analogues within the range of concentrations examined was practically absent, while the antibacterial activity was preserved. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 5; see also http: // www.maik.ru.
Assuntos
Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/síntese química , Peptídeos Catiônicos Antimicrobianos/isolamento & purificação , Bioquímica/métodos , Células Cultivadas , Cromatografia Líquida de Alta Pressão/métodos , Relação Dose-Resposta a Droga , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Triptofano/químicaRESUMO
Neuropeptide galanin produces a antipyretic effect in experimental pyrogenic reaction induced by intraperitoneal injection of lipopolysaccharide. Central intracerebroventricular injection of 100 ng galanin significantly attenuated, but did not completely abolish fever. Central galanin injection potentiated endotoxin-induced activation of the noradrenergic system and blocked activation of the serotoninergic system of the anterior hypothalamus.
Assuntos
Febre/tratamento farmacológico , Galanina/uso terapêutico , Animais , Temperatura Corporal/fisiologia , Cromatografia Líquida de Alta Pressão , Febre/induzido quimicamente , Galanina/farmacologia , Hipotálamo Anterior/metabolismo , Lipopolissacarídeos , Masculino , Neurotransmissores/metabolismo , Ratos , Ratos WistarRESUMO
In this work polyfunctional peripheral (pancreas) and central effects of galanin 1-29 (gal.) were reviewed. In hypothalamus gal. exerts neuroendocrine effects through modulation of secretion of principal hormones of hypophysis, co-localized with acetylcholine in some brain structures including hippocampus. Gal. influences behaviour and memory. Newest hypotheses of T. Hokfelt and J. N. Crawely [correction of G. Crowly] on the involvement of gal. to pathogenesis of in Alzheimer disease and possibilities of its clinical antiamnestic utility are discussed. Our own data indicates antiseizure effect of gal. in the model of febrile convulsions in children--hyperthermia induced seizures in neonatal rats in the age from 5 to 13 days. Systemic intraperitoneal administration of gal. was effective in certain age--7-11 days of postnatal period--in preventing hyperthermia induced seizures: in increased by 2-3 times latency of minimal seizures and clonic-tonic generalized seizures. In adults rats gal. showed antiseizure action when administered intranasal in the model of pentilenetetrazol seizures (modified test with repeated administration of subthreshold doses). Modern data on structure and function of galanin, its chimeric analogs and galanin receptors receptors are discussed.
Assuntos
Encéfalo/crescimento & desenvolvimento , Galanina/fisiologia , Convulsões/fisiopatologia , Animais , Anticonvulsivantes/uso terapêutico , Comportamento Animal/fisiologia , Encéfalo/efeitos dos fármacos , Criança , Galanina/farmacologia , Galanina/uso terapêutico , Humanos , Memória/fisiologia , Ratos , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológicoRESUMO
The effect of modified forms of vasopressin (MFV) that do not possess hormonal activity on homeostasis in rats was studied. One of the major effects of vasopressin (AVP) and its analogs on the blood clotting system, changes in fibrinolytic activity (FA) and the activity of plasminogen activator (APA), depends on modifications of the amino acid sequence in the peptide molecule. The presence of glycinamide in the AVP molecule enhances FA and APA. AVP molecules without the glycinamide group exert a more marked influence on procoagulant activity in blood.
Assuntos
Hemostasia/efeitos dos fármacos , Vasopressinas/farmacologia , Sequência de Aminoácidos , Animais , Dados de Sequência Molecular , Ratos , Relação Estrutura-Atividade , Fatores de TempoAssuntos
Coagulação Sanguínea/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Trombina/farmacologia , Timosina/farmacologia , Sequência de Aminoácidos , Humanos , Técnicas In Vitro , Dados de Sequência Molecular , Inibidores da Agregação Plaquetária/farmacologia , Trombina/antagonistas & inibidoresRESUMO
L-lysine-alpha-oxidase from Trichoderma sp. fungi inhibits the synthesis of DNA, RNA and protein in cultivated cells of the Burkitt lymphoma (strain P3HRj) in vitro, which results in the blocking of the cells' transfer from phase S to phase G2/M of the mitotic cycle.
Assuntos
Aminoácido Oxirredutases/toxicidade , Linfoma de Burkitt/patologia , Linfoma de Burkitt/metabolismo , Ciclo Celular/efeitos dos fármacos , Células Cultivadas , DNA de Neoplasias/biossíntese , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Proteínas de Neoplasias/biossíntese , RNA Neoplásico/biossíntese , Fatores de Tempo , Trichoderma/enzimologiaRESUMO
The data on the study of various soils and substrates for isolation of Micromonospora from them are presented. It was shown that Micromonospora predominated in moist soils and especially in such substrates as silts where their content with respect to the all actinomycetous isolates amounted to 88.9 per cent. In the silts the content of Micromonospora amounted to 66.6--83 per cent, in the sopromely its content was 66 per cent, while in the ordinary non-moist soil its content was from 6 to 11 per cent. Predominance of Micromonospora in silts and moist soils makes its directed search possible.