SARS-COV-2 Coronavirus Papain-like Protease PLpro as an Antiviral Target for Inhibitors of Active Site and Protein-Protein Interactions.

The papain-like protease PLpro of the SARS-CoV-2 coronavirus is a multifunctional enzyme that catalyzes the proteolytic processing of two viral polyproteins, pp1a and pp1ab. PLpro also cleaves peptide bonds between host cell proteins and ubiquitin (or ubiquitin-like proteins), which is associated with a violation of immune processes. Nine structures of the most effective inhibitors of the PLpro active center were prioritized according to the parameters of biochemical (IC 50) and cellular tests to assess the suppression of viral replication (EC 50) and cytotoxicity (CC 50). A literature search has shown that PLpro can interact with at least 60 potential protein partners in cells, 23 of which are targets for other viral proteins (human papillomavirus and Epstein-Barr virus). The analysis of protein-protein interactions showed that the proteins USP3, UBE2J1, RCHY1, and FAF2 involved in deubiquitinylation and ubiquitinylation processes contain the largest number of bonds with other proteins; the interaction of viral proteins with them can affect the architecture of the entire network of protein-protein interactions. Using the example of a spatial model of the PLpro/ubiquitin complex and a set of 154 naturally occurring compounds with known antiviral activity, 13 compounds (molecular masses in the range of 454-954 Da) were predicted as potential PLpro inhibitors. These compounds bind to the "hot" amino acid residues of the protease at the positions Gly163, Asp164, Arg166, Glu167, and Tyr264 involved in the interaction with ubiquitin. Thus, pharmacological effects on peripheral PLpro sites, which play important roles in binding protein substrates, may be an additional target-oriented antiviral strategy.

Dependence of protective functions of Escherichia coli polyamines on strength of stress caused by superoxide radicals.

Mechanisms of antioxidant effect of polyamines were studied in dependence on the strength of superoxide stress. Under conditions of weak stress, polyamines from Escherichia coli cultures were shown to function mainly as a scavenger of free superoxide radicals, whereas under conditions of strong stress they mainly acted as positive modulators of antioxidant genes. Spectrofluorimetry was used to show that both polyamine-dependent mutants and wild type cells treated with inhibitors of polyamine synthesis contained an elevated amount of free oxygen radicals, which could be decreased to the normal level by addition of exogenous polyamines. Under conditions of strong stress, polyamines positively influenced expression of the soxRS regulon genes of antioxidant defense, which was accompanied by an increase in the quantity (activity) of their gene products, such as glucose-6-phosphate dehydrogenase (Zwf) and fumarase (FumC). These effects led to an increase in the number of live cells in the cultures subjected to superoxide stress.

Inflammatory degeneration of joint tissue in adjuvant arthritis after intraarticular treatment with the mixture of silver drug and nicotinic acid.

Combination intraarticular administration of Poviargol (0.5 mg/kg) and nicotinic acid (1.0 mg/kg) reduced symptoms of local and general inflammation in rats with adjuvant arthritis. We revealed a decrease in morphological signs of inflammatory degeneration of joint tissue and reduction of metabolic disorders.

[Tuberculous meningitis in infants]. / Tuberkuleznyi meningit u detei rannego vozrasta.

Tuberculous meningitis (TM) develops more frequently in unvaccinated or inadequately vaccinated infants (28 cases of 34), in contact infants (26 of 34 cases). Within the first year of life TM is especially aggressive. Late diagnosis and treatment leave significant residual neurological changes or result in lethal outcomes.