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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. Other proteins that are responsible for the delivery of iron to cells and its balance between bacteria and the host organism also attract certain particular interest. The review summarizes data on the development of inhibitors and inducers (activators) of heme oxygenases, selective for mammals and bacteria, and considers the characteristic features of their mechanisms of action and structure. Based on the reviewed literature data, it was concluded that the use of hemin, the most powerful hemooxygenase inducer, and its derivatives as potential antimicrobial and antiviral agents, in particular against COVID-19 and other dangerous infections, would be a promising approach. In this case, an important role is attributed to the products of hemin degradation formed by heme oxygenases in vitro and in vivo. Certain attention has been paid to the data on the antimicrobial action of iron-free protoporphyrinates, namely complexes with Co, Ga, Zn, Mn, their advantages and disadvantages compared to hemin. Modification of the well-known antibiotic ceftazidime with a siderophore molecule increased its effectiveness against resistant bacteria.

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. Arginine-containing hemin conjugates demonstrated high antibacterial activity against Gram-positive bacteria including methicillin- and vancomycin-resistant strains in vitro. Most of the synthesized conjugates showed low toxicity against human erythrocytes and leukocytes., (© 2013 John Wiley & Sons A/S.)

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.

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. The HEM catalytic activity was characterized by two independent parameters: by reactivity and by its resistance to degradation. Both parameters were found to be pH-dependent. The reactivity was expressed as the effective rate constant for the reaction of HEM with lipid hydroperoxide. The resistance to degradation was characterized by the rate of the decrease in RIN with time and also by the regeneration coefficient, which shows how many active free radicals can be generated by one molecule of HEM. Both Hemin and metMB were found to be very effective catalysts even at nanomolar concentrations. The effective regeneration of active forms of HEM was observed. The catalytic activity of HEM was rapidly reduced with time. The kinetic scheme of the process under consideration was suggested, and this was applied for kinetic computer simulations.

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. Preliminary information confirming an oxidative mechanism of this process was obtained. The cleavage of plasmid DNA under the action of hemin peptides was studied by the methods of electron microscopy, gel electrophoresis, and atomic force microscopy.

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%. In comparison to the reference drug sodium cromoglycate, ingamine (in equimolar doses) showed a higher activity with respect to the antigen-dependent bronchospasmic reactions. It can be expected that ingamine will provide for the effective treatment of bronchial obstruction under clinical conditions.

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. It was shown that the gamma-L-Glu-HA derivative II can prevent totally or substantially a decrease in the NK activity. This agent also prevents inhibition of synthesis of alpha- and gamma-IFN during the post-stress period. The gamma-L-Glu-HA derivatives II, III, and VII increased the mice resistance to influenza virus type A/Aichi at low infection dose (10LD50). The derivative II showed its protective effect even at high dose of pathogen (100LD50). However, this gamma-L-Glu-HA derivative was virtually ineffective under harsh experimental conditions. Thus, a number of gamma-L-Glu-HA derivatives tested in this work demonstrated immunomodulation activity. These agents were able to normalize parameters of nonspecific immunity. They exerted a pronounced antiviral effect against influenza virus but were virtually ineffective against encephalitis in mice caused by herpes simplex virus, type 1. Of all tested agents, gamma-L-Glu-HA derivative II was found to be the most promising.

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. As a result, the number of melanosome-containing cells was 3-4 times and the number of melanosomes in them--5 times those in intact controls. Dicarbamine effect was double that of PTRA.

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 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.

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. It was investigated the influence of gamma-L-glutamyl-histamine on the severity of experimental anaphylactic reaction, hormonal content in blood plasma and liver cytochrome P-450. The induction of liver cytochrome P-450, the elevation of hormonal content (thyroxine and glucocorticoids) in blood plasma and decrease of the severity of experimental anaphylactic reaction are observed.

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.

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. The arachidonic acid metabolites regulate the activity of the ionic channels. It is demonstrated that derivatives of arachidonic acid have the role in the pathogenesis of hypertension.

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. NAC showed dose-dependent hydrolysis in its passage from the cornea to the aqueous humor, releasing C after 15. 30 min of ocular administration of prodrug in a series of therapeutical modalities: instillation < or = subconjunctival injection < or = ultrasound induced phoresis. Different treatment techniques showed excellent toleration of 1% NAC by the eye. Once in the aqueous humor, C might act as an antioxidant and enter the lens tissue when present at effective concentrations (5-15 mmol/l). The advantage of the ophthalmic prodrug NAC and its bioactivated principle C as universal antioxidants relates to their ability to give efficient protection against oxidative stress both in the lipid phase of biological membranes and in an aqueous environment. NAC is proposed to treat ocular disorders which have the component of oxidative stress in their genesis (cataracts, glaucoma, retinal degeneration, corneal disorders, ocular inflammation, complications of diabetes mellitus, systemic diseases).

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. The structural elements and conformations that are preferable for the appearance of antioxidant activity were found.

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(-.)-dependent iron-ascorbate and lipid-peroxyl-radical-generating linoleic acid 13-monohydroperoxide (LOOH)-activated haemoglobin systems, as measured by thiobarbituric-acid-reactive substance. Carcinine and carnosine are good scavengers of OH. radicals, as detected by iron-dependent radical damage to the sugar deoxyribose. This suggests that carnosine and carcinine are able to scavenge free radicals or donate hydrogen ions. The iodometric, conjugated diene and t.l.c. assessments of lipid hydroperoxides (13-monohydroperoxide linoleic acid and phosphatidylcholine hydroperoxide) showed their efficient reduction and deactivation by carnosine and carcinine (10-25 mM) in the liberated and bound-to-artificial-bilayer states. This suggests that the peroxidase activity exceeded that susceptible to direct reduction with glutathione peroxidase. Imidazole, solutions of beta-alanine, or their mixtures with peptide moieties did not show antioxidant potential. Free L-histidine and especially histamine stimulated iron (II) salt-dependent LPO. Due to the combination of weak metal chelating (abolished by EDTA), OH. and lipid peroxyl radicals scavenging, reducing activities to liberated fatty acid and phospholipid hydroperoxides, carnosine and carcinine appear to be physiological antioxidants able to efficiently protect the lipid phase of biological membranes and aqueous environments.

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. The peptides and their conjugates with BSA or KLH were used for ELISA with individual and pooled anti-HD-positive sera from patients with chronic delta hepatitis. The high antigenicity of the peptide 65-80 shows that one of the antigenically active regions of HDAg is situated between these amino acid residues and that the peptide may be used for detection of anti-HD antibodies in patients blood sera.

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. The resultant antibodies were shown to react with peptides. The blood sera from patients with acute hepatitis B reacted with the conjugates of peptides 24-41, 30-36, 31-36 in the immunoenzymic solid phase assay. The monoclonal antibodies for the preS1-polypeptide were shown to react with peptides 24-41, 30-36, 31-36 and with their conjugates. The results obtained were proved by the data of the epitope-mapping with overlapping hexapeptides.

We have synthesized the 24-41 fragment of the preS region of the hepatitis B (subtype ayw) envelope. The peptide was prepared by the solid phase synthesis on perfluoropoly-ethylene polymer grafted with polystyrene. The peptide chain was elongated from C-terminus using pentafluorophenyl- and p-nitrophenyl esters of Boc-amino acids. The peptide was cleaved off the solid phase by HBr in CF3COOH, purified by gel filtration, and, after conjugation with serum albumin (BSA), inoculated into mice. The resultant antibodies were shown to react with the peptide. The blood sera from patients with acute hepatitis B reacted with the peptide-BSA conjugates in the immunoenzymic solid phase assay.