Volume 42, Nº 4 (2016)

Antimicrobial peptides (AMPs) of invertebrates are characterized by a wide variety of mechanisms of their action that involve not only disruption of the barrier function of a membrane of a target cell, but specific inhibition of metabolism processes via ligand-receptor interactions with specific molecules on the surface or within the cell as well. Endogenous AMPs can play a role of mediators of the immune system (immunomodulators) by activation of phagocytosis and chemotaxis, and by stimulation of production of cytokines. The second part of the review focuses on biological functions and mechanisms of action of AMPs of invertebrates. A problem of biological significance of antimicrobial properties in vitro is reviewed. The main mechanisms of the AMP action on a membrane (models of the barrel-stave channel and the toroidal pore and the “carpet” mechanism) are described, and the problems of selectivity of interaction with a microbial membrane are analyzed. The data on alternative mechanisms of the antimicrobial action, such as inhibition of transcription and translation, sequestration of metal ions, and inhibition of biosynthesis of bacterial and fungal cell walls, are presented. A number of examples demonstrate the AMP regulatory activities of invertebrates.

We found a unique property of E. coli purine nucleoside phosphorylases to selectively perform the arsenolysis reaction of ribonucleosides in their active site without affecting β-D-arabinonucleosides. In the synthesis of modified β-D-arabinonucleosides from the corresponding ribonucleosides, the catalytical amount of sodium arsenate in the transglycosylation reaction provided a 95 to 98% conversion rate. Such an approach was shown to simplify the composition of the reaction mixtures and facilitate the isolation of the target nucleosides, particularly, vidarabine, fludarabine, and nelarabine.

The activity of caspase-3, caspase-8, superoxide dismutase, and catalase and the content of circulating immune complexes and immunoglobulins A, M, and G in the blood serum and muscles of rats in the norm, in experimental rheumatoid arthritis, and by the action of lipoic acid against the background of progressive pathology have been studied. The induction of rheumatoid arthritis in rats was accompanied by an increase in marker parameters and immune status indices, as well as in the activity of caspase-3, caspase-8, superoxide dismutase, and catalase, which was probably caused by excessive generation of reactive oxygen species during the development of pathology. The administration of lipoic acid to rats with rheumatoid arthritis led to a normalization of the parameters, which was evidently due to the capacity of the compound to produce the antioxidant effect and reduce the severity of autoimmune diseases.

A series of target-oriented competitive inhibitors of human soluble epoxide hydrolase have been synthesized. The compounds retain the inhibitory properties at concentrations down to 4 nM. Based on the results of molecular modeling, it has been shown that the high inhibitory activity of this series of compounds is achieved by a unique mode of the binding to the active site of the enzyme.

Earlier unknown 1,12-diamino-2,11-bis(methylidene)-4,9-diazadodecane, which may be considered as an enzyme-activated inhibitor of spermine oxidase, was synthesized in 6 steps starting from 2-chloromethyl-3-chloropropene-1 in a high yield. Application of newly synthesized spermine analogue for the inhibition of spermine oxidase was discussed.

A novel series of thiourea, carbamimidothioic acid, 4, 5-dihydrooxazole-2-thiol, oxazolidine-2thine, and 2-amino-1-phenylpropyl-2-chloroacetate derivatives was designed and synthesized using 2-amino-1-phenylpropan-1-ol (L-norephedrine) as a strategic starting material. The structures of the newly synthesized compounds were established by elemental analyses, IR, and ¹H NMR and ¹³C NMR spectral data. The compounds were evaluated for their in vitro anticancer activity against various cancer cell lines. The corresponding acetamide, carbamimidothioic acid, and 2-2-amino-1-phenylpropyl-2-chloroacetate derivatives showed almost the same activity as the standard drug doxorubicin against human breast cancer cell line (MCF-7). Also, the acetamide and 2-thioxoimidazolidin-4-one derivatives exhibited higher activity than the reference drug doxorubicin against human colon cancer cell line (HCT 116).

Receptor tyrosine kinase IRR is a pH-sensor that able to be activated by alkaline extracellular media. IRR is a close homologue of the insulin receptor and insulin-like growth factor receptor but no endogenous ligands of a peptide or protein nature have been found for IRR. IRR expression was detected in certain populations of kidney cells, stomach, pancreas and also in parts of the sympathetic and cholinergic neurons. We have previously identified behavioral disorders in mice lacking IRR. In this study we performed a comparative analysis of wild-type mice brain transcriptomes and IRR-knockout mice brain transcriptomes using method of deep sequencing. The most significant difference (two-fold increase in expression) was observed for Ly6/PLAUR protein transcript. It is known that this protein is able to stimulate nicotinic acetylcholine receptor desensibilization. These results suggest that behavioral characteristics of mice lacking IRR are caused by the functional link between IRR and Ly6/PLAUR in cholinergic neurons of the brain.