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.

Accumulated morbidity prevention priorities determining by losses and acquisitions indexing

Background. Determine the diagnostic and prophylaxis potential of the algorithm for indexing losses and acquisitions of the adult population in relation to the accumulated morbidity. Materials and methods. 1369 respondents (697 men and 672 women) aged 18 to 59 years were interviewed, all of them were randomized into 3 groups. 113 persons with an losses and acquisitions index (LAI) less than “0” were included in the first group, 582 respondents with an LAI = 0 made up the second group, 674 respondents with an LAI more than “0” were collected in the third group. The study was conducted with the approval of the Independent Ethical Committee of the Federal State Budgetary Educational Institution of Higher Education of the Rostov State Medical University of the Health Ministry of Russia (rector-MD, professor Shlyk S.V.). Each participant signed an informed consent form to participate in the survey, according to the Declaration of Helsinki of the World Medical Association, which regulates conduct research. The indexing of losses and acquisitions was carried out using a structured indicator consisting of an affiliative (close person, team, motherland) and pragmatic parts (job, money, durable goods). The assessment of the diagnostic significance of LAI was carried out by the method of determining the accumulated morbidity. Statistical data processing was carried out using the Excel software package Microsoft Office 2010. Results. Indexing the level of health by fixing objectified (realized) motives in a state of loss or acquisition made it possible to record a significant decrease in cumulative morbidity by 43.6% with LAI increase from level-1 to level +1, while acquisitions generally influenced the accumulated morbidity rate in 8.4 times weaker than losses. On the other hand, the intensity of pragmatic acquisitions was correlated with improved health with minimal standard error (Sr = 0.036). Given the randomized nature of the sample, it can be argued that at the time of the study, the loss of loved ones increased the accumulated morbidity in the population (in terms of growth rate) by 7.1 times less than the loss of work, money or durable goods. Conclusion. Mathematical modeling of the process of interaction between the accumulated morbidity (AM) and socially significant objects (SSO) lost or acquired by respondents (y =-0.333x + 1.818) with high reliability (admitting an error probability of 5%) shows that the health level of modern Russian society is extremely sensitive to changes in socio-economic situation, which we diagnosed with the help of LAI and found that each step on the losses and acquisitions scale (1 SSO) changes AM by 333 ‰. In other words, at the time of observation, the focus of society on the acquisition of material wealth (the desire to satisfy the ever-increasing material needs) was noted. At the same time, the deepening economic crisis (especially against the backdrop of the COVID-19 pandemic) has significantly increased the risks of acquiring new diseases, since the cases of material losses have also become more frequent. In our opinion, the chain of cause and effect, starting with material losses (as the most sensitive in medical terms) is available for active correction. Measures containing educational and cultural and upbringing content that can replace the health-destructive priorities of acquisition with health-preserving altruistic values, can replace the lost pragmatic SSO with acquired affiliative ones, can become the main direction of such correction (prevention). The greatest effect of measures for the primary prevention of pragmatization and the subsequent medical failure of society is expected in children and adolescents social groups. © 2021, Science and Innovation Center Publishing House. All rights reserved.