Novosibirsk State University

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the third case of widespread coronavirus infection. Together with the other two viruses, the SARS-CoV-2 virus is highly pathogenic, and some strains have a mortality rate of more than 1%. Moreover, it has become clear that coronaviruses mutate quite often, which reduces the effectiveness of available vaccines and forces the regular creation of new ones. The main viral protease M^pro is a suitable target for direct-acting drugs. Currently, there is only one recommended anticoronavirus drug, nirmatrelvir, which, however, does not have all the properties necessary for widespread and effective use. Thus, the development of a highly selective and effective protease inhibitor that can be taken orally still remains relevant. In this work, we performed an in-depth literature review of M^pro inhibitor studies and conducted extensive molecular dynamics simulations of M^pro-inhibitor complexes with computational prediction of binding ability and ADME (absorption, distribution, metabolism and excretion) properties of new compounds. On the basis of the literature review we composed a set of criteria that a potent inhibitor must meet. Then we created a set of possible inhibitors and their parts, which presumably allows all the necessary properties, namely, high affinity for the viral enzyme, selectivity, bioavailability and solubility, to be achieved.

Long noncoding RNAs (lncRNAs) are increasingly recognized for their roles in regulating gene expression, yet they remain poorly understood, especially in non-human species. This study investigates the lncRNA Bdnf-as in rats, which modulates the transcription of the Bdnf gene through interactions with chromatin remodelers.

In this study, we employed a variety of methodologies to identify novel antisense transcripts of Bdnf-as in the rat genome. These methodologies included step-out rapid amplification of cDNA ends, lentivirus infusion in the neonatal rat prefrontal cortex (PFC), TET-on construct expression induction with doxycycline, de novo transcriptome assembly, and bioinformatics analysis. Our findings, derived from these rigorous methods, have led to the identification of two novel antisense transcripts of Bdnf-as in the rat genome.

These transcripts, located downstream of the Bdnf coding region, exhibit splicing and appear to be influenced by overexpression of proBDNF. The application of reverse transcription from gene-specific primers in conjunction with quantitative polymerase chain reaction (qPCR) analysis revealed that Bdnf-as exhibited augmented expression exclusively following proBDNF expression induction from a lentiviral construct, and not in the presence of a mutated form. A bioinformatic analysis revealed the potential binding of the following proteins to this site: E2F1, VDR, SP3, ZNF354C, YY2, SPI1, RUNX1, and TBX3. A comparative genomic analysis revealed limited evolutionary conservation of Bdnf-as between rats, humans, and mice, reflecting the rapid divergence of lncRNAs. The analysis of RNAseq data indicates that Bdnf-as is expressed at low levels and is likely unstable, a factor that could contribute to its detection challenges.

The present findings offer the initial characterization of rat Bdnf-as, its differential expression depending on expression construct, thus establishing the foundation for future studies to explore its regulatory functions and protein interactions in neurobiological processes.

The study presents the discovery of a novel class of N-arylated 1,2,4-oxadiazol-5(4H)-ones as potent inhibitors of orthopoxviruses, including the variola virus (VARV). Through systematic structural modifications, two lead compounds, 4 (4-CF₃/4-NO₂) and 10 (4-I/4-NO₂), demonstrated in submicromolar concentration antiviral activity against Vaccinia virus (VACV), cowpox virus (CPXV), ectromelia virus (ECTV), and VARV, with selectivity indices (SI) up to 13738. Studies of mechanisms of action, including time-of-addition experiments and molecular modeling, have shown that these compounds can target the conserved protein p37, which plays a key role in the envelope of the virus. Furthermore, bioinformatic analysis revealed potential interactions with late-stage replication proteins encoded by the A39R and C8L genes. The synthesized derivatives showed activity higher than that of Cidofovir, although they were less effective than that of Tecovirimate. This work highlights the potential of oxadiazolone-based scaffolds as broad-spectrum antipoxviral agents that meet the unmet need for therapy against emerging and re-emerging orthopoxviral threats.