Iron metabolism in the cell as a target in the development of potential antimicrobial and antiviral agents.

The search and creation of innovative antimicrobial drugs, acting against resistant and multiresistant strains of bacteria and fungi, are one of the most important tasks of modern bioorganic chemistry and pharmaceuticals. Since iron is essential for the vital activity of almost all organisms, including mammals and bacteria, the proteins involved in its metabolism can serve as potential targets in the development of new promising antimicrobial agents. Such targets include endogenous mammalian biomolecules, heme oxygenases, siderophores, protein 24p3, as well as bacterial heme oxygenases and siderophores.

Synthesis, anti-MRSA, and anti-VRE activity of hemin conjugates with amino acids and branched peptides.

The increasing prevalence of antibiotic-resistant bacterial strains has necessitated the synthesis of novel antibacterial agents. It was previously shown that naturally occurring metalloporphyrin hemin possesses dark antibacterial activity against Gram-positive bacteria. To improve hemin antibacterial activity, we synthesized a number of hemin conjugates with amino acids and branched peptides.

[Antimicrobial peptides: mode of action and perspectives of practical application].

This review is devoted to antimicrobial peptides (AMP's) that demonstrate activity against bacteria, viruses and fungi. It considers structure and mechanism of AMP interaction with lipid membrane and intracellular targets of pathogens. Special attention is paid to modem state and perspectives of AMP practical application and also to approaches that increase efficacy and reduce toxicity of AMP by chemical modification of their structure.

Efficacy of metmyoglobin and hemin as a catalyst of lipid peroxidation determined by using a new testing system.

A new quantitative approach to investigate the capability of iron heme complexes (HEM), metmyoglobin and hemin, to catalyze lipid peroxidation was elaborated. The oxidation of methyl linoleate in micellar solutions was used as a testing model. The key point was the determination of the rate of free radical generation, RIN, calculated from the rate of oxygen consumption.

[Synthesis and structure-function study of artificial nucleases on the basis of hemin conjugates with peptide fragments of cell differentiation factor HLDF].

A series of octa-hexapeptide fragments of HLDF and their conjugates with hemin were obtained by solid phase peptide synthesis. A relationship between the structure and the nuclease activity of the compounds was established. The effect of various factors (medium pH, the presence of metal ions, complexons, reducers, and buffer composition) on DNA destruction with hemin peptides was studied.

[The protector properties of a pseudopeptide drug ingamine studied on a model of bronchospasm in guinea pigs].

The original pseudopeptide drug ingamine (4-[N-[2-(imidazol-4-yl)ethyl]-carbamoyl] butyric acid) was studied on the traditional model of antigen-induced bronchospasm in actively sensitized guinea pigs. The drug was introduced using various methods (by inhalation, via intragastric tube, and by intraperitoneal injections) in a range of doses (20, 50, 150, or 500 mg/kg). The new drug exhibited a pronounced dose-dependent protector action for all ways of introduction, but the most significant effect was observed upon inhalation, whereby the degree of bronchospasm inhibition exceeded 80%.

[Cell differentiation in human melanoma cells caused by dicarbamine (ultrastructural investigation)].

The effects of dicarbamine (r) and polytransretinoic acid (PTRA) on human melanoma MEL-6 transplanted into Balb/c nude female mice have been compared by histological and electron microscopic procedures. It was discovered that long-term administration of 1.5 mg/kg dicarbamine caused melanoma MEL-6 cells to undergo terminal differentiation.

[Antiviral and anti-stress activity of the gamma-L-glutamyl-histamine and its derivatives].

Effect of gamma-L-glutamylhistamine gamma-L-Glu-HA and some of its derivatives on the state of nonspecific resistance and antiviral activity was studied using experimental models of influenza virus and herpes simplex virus infections. Activities of natural killer (NK) cells and interferon (IFN) system were measured. The model of physical-emotional stress in mice was used.

[Hepatoprotective effects of gamma-L-glutamylhistamine].

The influence of gamma-GluHA and glutarylhistamine on the lipid peroxidation, cholesterol, phospholipid and liver aminotransferase activity was investigated using carbon tetrachloride-induced model of subacute liver damage. Pretreatment of rats with gamma-GluHA and glutarylhistamine prevented liver necrosis and normalized activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in blood plasma, lipid peroxidation in the liver and plasma, lipid profiles and cholesterol content in the liver and plasma.

[The effect of gamma-L-glutamylhistamine analogues on the severity of experimental anaphylactic reaction, hormonal status and liver cytochrome P450 system].

The influence of gamma-L-glutamylhistamine analogues on the hexenal-induced sleeping, glucocorticoid hormone content in blood plasma and severity of experimental anaphylactic reaction was studied. It was observed that gamma-L-glutamylhistamine analogues caused decrease in the sleeping time and severity of experimental anaphylactic reaction, the elevation of glucocorticoids content in blood plasma. The present results indicate that substances have the wide spectrum of biological activity which depends on the length of the N-acyl radical.

[The effect of gamma-L-glutamyl histamine on the severity of experimental anaphylactic reaction, hormonal status and liver cytochrome p-450].

gamma-L-Glutamyl-histamine (gamma-GluHA) was synthesized at Department of the chemistry and technology of fine organic compounds M. V. Lomonosov Moscow state academy of fine chemical technology.

[Synthesis of arginine-containing peptides and their conjugates with protohemin IX and tetraphenylporphyrin].

Arg-containing peptides and their conjugates with protohemin IX were synthesized by the solid phase method using Merrifield resin. The conjugates of Arg-containing peptides with tetraphenylporphyrin were obtained by using phosphorus trichloride as an activating agent.

[Effect of cytochrome P450-dependent metabolites of arachidonic acid on the functional state of vessels].

The present paper reviews recent studies about the role of the cytochrome P-450-dependent arachidonic acid metabolites. There metabolites take part in the regulation of the vascular tone. They are the intracellular messenger and play an integral role in the relation of the vascular endothelium and smooth muscle cells.

N alpha-acetylcarnosine is a prodrug of L-carnosine in ophthalmic application as antioxidant.

The naturally occurring compound N alpha-acetylcarnosine (NAC) is proposed as the prodrug of L-carnosine (C) resistant to enzymatic hydrolysis by human serum carnosinase. Rabbit eyes were treated with 1% NAC, C or placebo and extracts of the aqueous humor from the anterior eye chamber were analyzed for imidazole content by reverse phase analytical high performance liquid chromatography (HPLC), thin-layer (TLC) and ion-exchange chromatographic techniques. The topical administration of pure C to the rabbit eye did not lead to accumulation of this compound in the aqueous humor over 30 min in concentration exceeding that in the placebo-treated matched eye.

[Relation between the conformation and antioxidant properties in a series of topochemical analogs of carnosine and carcinine with different N-acyl substitutes].

To elucidate the influence of the nature of N-acyl substituent on antioxidant properties of carcinine analogs, the corresponding histamine derivatives were synthesized. Antioxidant activity of the compounds prepared was investigated in the Fe(2+)-ascorbate-dependent system of oxidation of the linoleic acid micellar solution. Conformations of carnosine, carcinine, and their analogs were calculated by the molecular mechanics MM+ method.

L-carnosine (beta-alanyl-L-histidine) and carcinine (beta-alanylhistamine) act as natural antioxidants with hydroxyl-radical-scavenging and lipid-peroxidase activities.

Carnosine (beta-alanyl-L-histidine) and carcinine (beta-alanylhistamine) are natural imidazole-containing compounds found in the non-protein fraction of mammalian tissues. Carcinine was synthesized by an original procedure and characterized. Both carnosine and carcinine (10-25 mM) are capable of inhibiting the catalysis of linoleic acid and phosphatidylcholine liposomal peroxidation (LPO) by the O2(-.

[Synthesis and antigenic activity of peptides of the nucleocapsid protein of the hepatitis delta virus].

Hepatitis delta virus (HDV), a recently discovered infectious agent, participates in severe, often lethal forms of acute and chronic hepatitis and liver cirrhosis. Based on theoretical analysis of secondary structure, hydrophilicity and acrophilicity data, several regions of HDV antigen, presumably containing B-epitopes, have been revealed and the corresponding peptides have been synthesized by the solid phase method. All the peptides obtained reacted with the respective antipeptide rabbit sera.

[Synthesis of peptides of the preS1-region of the viral hepatitis B envelope protein and localization of antigenic determinants].

We synthesized the 24-41, 30-36, 31-36, 24-30 fragments of the preS1-region of the hepatitis B (subtype ayw) envelope. The peptides were prepared by the solid phase synthesis on perfluorpolyethylene polymer grafted with polystyrene. The peptide chains were elongated from C-terminus using activated esters and symmetrical anhydrides of Boc-amino acids, cleaved off the solid phase by HBr or TFMSA in TFA, purified by gel filtration, and, after conjugation with protein carriers, inoculated into test animals.