[Immunotherapy for infectious diseases: challenges and prospects].

The fact that many infectious diseases are not effectively controlled with etiotropic drugs determines the relevance of a search for alternative methods, particularly those based on the modulation of immunity. The review analyzes rational approaches to the immunotherapy of infectious diseases, such as regulation of acquired immunity; correction of the quantitative and qualitative composition of the intestinal microbiota; and modulation of innate immunity. Among the drugs affecting the innate components of an immune response, the derivatives of muramyl dipeptide (MDP), a structural subunit of bacterial cell wall peptidoglycan, stand out in the context of a detailed study of the cellular and molecular mechanisms of action. The fact that it is expedient to clinically apply these immunomodulators in many diseases accompanied by inadequate infection control is beyond question. It is demonstrated that muramyl peptides (MP) may be also used to prevent excessive inflammatory responses. The adjuvant properties of MDP and its analogues can be employed for therapeutic vaccination. The data that the signals transmitted through NOD-like receptors (MP sensors) regulate intestinal homeostasis suggest that there is some potential for the use of MDP derivatives for the correction of dysbiosis and related immune disorders. Whatever the purpose of immunomodulation, the key to its effectiveness is to personalize the choice and regimens of immunotropic drugs.

[Synthesis and biological activity of aryl S-beta-glycosides of 1-thio-N-acetylmuramyl-L-alanyl-D-isoglutamine].

Phenyl, p-tolyl, and p-tert-butylphenyl beta-1-thio-N-acetylglucosaminides were synthesized by the treatment of thiophenols with peracetate of alpha-D-glucosaminyl chloride in the presence of triethylamine or under the conditions of phase-transfer catalysis with quaternary ammonium salts. The compounds synthesized were used for obtaining of glycosides of 4,6-O-isopropylidene-N-acetylmuramic acid, which were coupled with L-Ala-D-Glu(NH2)-OBzl and then deprotected to obtain the target aryl beta-thioglycosides of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP). The aryl beta-thioglycosides of MDP were found to stimulate an antibacterial resistance toward Staphylococcus aureus in mice. The reliable induction of the spontaneous activity of natural killers in the population of blood mononuclear cells was observed only for phenyl beta-thio-MDP at a dose of 200 microg/ml. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2008, vol. 34, no. 2; see also http://www.maik.ru.

[Dialkylmethyl beta-glycosides of N-acetylmuramyl-L-alanyl-D-isoglutamine: synthesis and infection protective and cytotoxic activities].

Symmetric secondary linear alcohols were proposed as aglycones for the synthesis of lipophilic beta-glycosides of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP). Pentadecan-8-ol, nonadecan-10-ol, and tricosan-12-ol were glycosylated by the oxazoline method. Based on the corresponding glucosaminides, alkyl beta-glycosides of 4,6-O-isopropylidene-N-acetylmuramic acid were synthesized and coupled with the dipeptide. Deprotection of isopropylidene groups by acidic hydrolysis and catalytic hydrogenolysis of benzyl esters resulted in the target muramyldipeptide glycosides. Nonadecan-10-yl and tricosan-12-yl [beta]-MDPs at doses 2 microg/mice most effectively stimulated antibacterial resistance in mice against Staphylococcus aureus. In contrast to the previously synthesized undecan-6-yl beta-MDP, pentadecan-8-yl, nonadecan-10-yl, and tricosan-12-yl beta-MDPs demonstrated direct cytotoxicity toward tumor cells E-562 and blood mononuclear cells.

[Synthesis and protective anti-infective action of anomeric lipophilic glycosides of N-acetylmuramyl-L-alanyl-D-isoglutamine].

Anomeric pairs of alpha- and beta-dodecyl, alpha- and beta-(1-pentylhexyl), and alpha- and beta-cyclododecyl glycosides of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) were synthesized. The starting beta-D-glucosaminides were obtained by the oxazoline method, and the corresponding alpha-isomers, by the mercuric iodide-catalyzed glycosylation of alcohols with alpha-glucosaminyl chloride peracetate in nitromethane at -90 degrees C. No reliable differences between the stimulation of mouse resistance to the infection with Staphylococcus aureus (doses of 2, 20, and 200 microg/mouse) and Escherichia coli (doses of 0.05, 1, and 20 microg/mouse) with the MDP alpha- and beta-glycosides were found.

[Synthesis and protective activity of beta-glycosides of N-acetylmuramyl-L-alanyl-D-isoglutamine with alkylalicyclic and arylaliphatic aglycons].

The following glycosides of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) were synthesized: beta-4-tert-butylcyclohexyl MDP, beta-2-(adamant-1-yl)ethyl MDP, beta-2,2-diphenylethyl MDP, and 3-2-(p-biphenyl)ethyl MDP. The starting peracetylated beta-N-acetylglucosaminides were prepared by the oxazoline method. They were converted into 4,6-O-isopropylidene-N-acetyl-D-muramic acids, which were coupled with L-Ala-D-Glu(NH2)OBn. The target glycopeptides were obtained after their deprotection. The stimulation of the antiinfection resistance of mice against Staphylococcus aureus by the MDP glycosides was studied. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2005, vol. 31, no. 6; see also http://www.maik.ru.

[N-acetylmuramyl-L-alanyl-D-isoglutamine glycosides. Effect of glycoside center configuration and aglycone nature on biological activity]. / Glikozidy N-atsetilmuramoil-L-alanil-D-izoglutamina. Vliianie konfiguratsii glikozidnogo tsentra i prirody aglikona na biologicheskuiu aktivnost'.

Hexyl, octyl, and cyclohexyl beta-glycosides and heptyl and cyclohexyl alpha-glycosides of muramyl dipeptide (MDP) were synthesized. Tests in vitro and in vivo revealed lower immunostimulating activities of MDP alpha-glycosides in comparison with the corresponding beta-glycosides and MDP itself. In the case of alkyl beta-glycosides, differences in hydrocarbon chain lengths (C4-C8) and in aglycone (aliphatic chain and aliphatic or aromatic ring) exerted no substantial effect on the immunostimulating activity.