Methyltransferases of Riboviria.

Many viruses from the realm Riboviria infecting eukaryotic hosts encode protein domains with sequence similarity to S-adenosylmethionine-dependent methyltransferases. These protein domains are thought to be involved in methylation of the 5'-terminal cap structures in virus mRNAs. Some methyltransferase-like domains of Riboviria are homologous to the widespread cellular FtsJ/RrmJ-like methyltransferases involved in modification of cellular RNAs; other methyltransferases, found in a subset of positive-strand RNA viruses, have been assigned to a separate "Sindbis-like" family; and coronavirus-specific Nsp13/14-like methyltransferases appeared to be different from both those classes. The representative structures of proteins from all three groups belong to a specific variety of the Rossmann fold with a seven-stranded ß-sheet, but it was unclear whether this structural similarity extends to the level of conserved sequence signatures. Here I survey methyltransferases in Riboviria and derive a joint sequence alignment model that covers all groups of virus methyltransferases and subsumes the previously defined conserved sequence motifs. Analysis of the spatial structures indicates that two highly conserved residues, a lysine and an aspartate, frequently contact a water molecule, which is located in the enzyme active center next to the methyl group of S-adenosylmethionine cofactor and could play a key role in the catalytic mechanism of the enzyme. Phylogenetic evidence indicates a likely origin of all methyltransferases of Riboviria from cellular RrmJ-like enzymes and their rapid divergence with infrequent horizontal transfer between distantly related viruses.

Relations between higher- and lower-order alcohol and cannabis expectancies and simultaneous use frequency among undergraduate dual users

Simultaneous alcohol and cannabis (i.e. marijuana;[SAM]) use is prevalent among college students. There is limited research on expectancy effects for SAM use, which are known correlates of use frequency and mediators of treatment outcomes. We examined the unique associations of both positive and negative alcohol and cannabis expectancies with frequency of SAM use among college students. Participants were 1012 college students (70.9% female, 51.8% white, Mage = 19.63) from seven US universities who reported past-month alcohol and cannabis use (77.2% of the sample reported SAM use). Students completed measures of past-month typical weekly alcohol and cannabis frequency and quantity, alcohol and cannabis expectancies, and SAM frequency through an online self-reported survey. A negative binomial regression revealed that higher-order positive, but not negative, alcohol and cannabis expectancies were significant predictors of SAM frequency above and beyond frequency of alcohol and cannabis use, biological sex, and whether the survey was completed pre- or post-COVID-19 campus closures. Specifically, higher frequency SAM use was associated with weaker positive alcohol and stronger positive cannabis expectancies. A second negative binomial regression including lower-order expectancies found that SAM frequency was associated with weaker social and cognitive and behavioral impairment alcohol expectancies and stronger sexual and social facilitation cannabis and liquid courage alcohol expectancies, specifically. Results highlight the importance of comprehensively examining both higher- and lower-order alcohol and cannabis expectancies when examining SAM frequency, and provide avenues of targeted intervention to reduce SAM use among dual users.

Epigenetic perspectives of COVID-19: Virus infection to disease progression and therapeutic control.

COVID-19 has caused numerous deaths as well as imposed social isolation and upheaval world-wide. Although, the genome and the composition of the virus, the entry process and replication mechanisms are well investigated from by several laboratories across the world, there are many unknown remaining questions. For example, what are the functions of membrane lipids during entry, packaging and exit of virus particles? Also, the metabolic aspects of the infected tissue cells are poorly understood. In the course of virus replication and formation of virus particles within the host cell, the enhanced metabolic activities of the host is directly proportional to viral loads. The epigenetic landscape of the host cells is also altered, particularly the expression/repression of genes associated with cellular metabolism as well as cellular processes that are antagonistic to the virus. Metabolic pathways are enzyme driven processes and the expression profile and mechanism of regulations of the respective genes encoding those enzymes during the course of pathogen invasion might be highly informative on the course of the disease. Recently, the metabolic profile of the patients' sera have been analysed from few patients. In view of this, and to gain further insights into the roles that epigenetic mechanisms might play in this scenario in regulation of metabolic pathways during the progression of COVID-19 are discussed and summarised in this contribution for ensuring best therapy.

Nutrition, Epigenetics, and Major Depressive Disorder: Understanding the Connection.

Major depressive disorder (MDD) is a complex, multifactorial disorder of rising prevalence and incidence worldwide. Nearly, 280 million of people suffer from this leading cause of disability in the world. Moreover, patients with this condition are frequently co-affected by essential nutrient deficiency. The typical scene with stress and hustle in developed countries tends to be accompanied by eating disorders implying overnutrition from high-carbohydrates and high-fat diets with low micronutrients intake. In fact, currently, coronavirus disease 2019 (COVID-19) pandemic has drawn more attention to this underdiagnosed condition, besides the importance of the nutritional status in shaping immunomodulation, in which minerals, vitamins, or omega 3 polyunsaturated fatty acids (ω-3 PUFA) play an important role. The awareness of nutritional assessment is greater and greater in the patients with depression since antidepressant treatments have such a significant probability of failing. As diet is considered a crucial environmental factor, underlying epigenetic mechanisms that experience an adaptation or consequence on their signaling and expression mechanisms are reviewed. In this study, we included metabolic changes derived from an impairment in cellular processes due to lacking some essential nutrients in diet and therefore in the organism. Finally, aspects related to nutritional interventions and recommendations are also addressed.

COVID-19 and One-Carbon Metabolism.

Dysregulation of one-carbon metabolism affects a wide range of biological processes and is associated with a number of diseases, including cardiovascular disease, dementia, neural tube defects, and cancer. Accumulating evidence suggests that one-carbon metabolism plays an important role in COVID-19. The symptoms of long COVID-19 are similar to those presented by subjects suffering from vitamin B12 deficiency (pernicious anemia). The metabolism of a cell infected by the SARS-CoV-2 virus is reshaped to fulfill the need for massive viral RNA synthesis, which requires de novo purine biosynthesis involving folate and one-carbon metabolism. Many aspects of host sulfur amino acid metabolism, particularly glutathione metabolism underlying antioxidant defenses, are also taken over by the SARS-CoV-2 virus. The purpose of this review is to summarize recent findings related to one-carbon metabolism and sulfur metabolites in COVID-19 and discuss how they inform strategies to combat the disease.

Virtual screening of molecular databases for potential inhibitors of the NSP16/NSP10 methyltransferase from SARS-CoV-2.

COVID-19 is a disease caused by the SARS-CoV-2 virus and represents one of the greatest health problems that humanity faces at the moment. Therefore, efforts have been made with the objective of seeking therapies that could be effective in combating this problematic. In the search for ligands, computational chemistry plays an essential role, since it allows the screening of thousands of molecules on a given target, in order to save time and money for the in vitro or in vivo pharmacological stage. In this paper, we perform a virtual screening by docking looking for potential inhibitors of the NSP16-NSP10 protein dimer (methyltransferase) from SARS-CoV-2, by evaluating a homemade databank of molecules found in plants of the Caatinga Brazilian biome, compounds from ZINC online molecular database, as well as structural analogues of the enzymatic cofactor s-adenosylmethionine (SAM) and a known inhibitor in the literature, sinefungin (SFG), provided at PubChem database. All the evaluated sets presented molecules that deserve attention, highlighting four compounds from ZINC as the most promising ligands. These results contribute to the discovery of new molecular hits, in the search of potential agents against SARS-CoV-2 virus, still unveiling a pathway that can be used in combined therapies.

Co-crystallization and structure determination: An effective direction for anti-SARS-CoV-2 drug discovery.

Safer and more-effective drugs are urgently needed to counter infections with the highly pathogenic SARS-CoV-2, cause of the COVID-19 pandemic. Identification of efficient inhibitors to treat and prevent SARS-CoV-2 infection is a predominant focus. Encouragingly, using X-ray crystal structures of therapeutically relevant drug targets (PLpro, Mpro, RdRp, and S glycoprotein) offers a valuable direction for anti-SARS-CoV-2 drug discovery and lead optimization through direct visualization of interactions. Computational analyses based primarily on MMPBSA calculations have also been proposed for assessing the binding stability of biomolecular structures involving the ligand and receptor. In this study, we focused on state-of-the-art X-ray co-crystal structures of the abovementioned targets complexed with newly identified small-molecule inhibitors (natural products, FDA-approved drugs, candidate drugs, and their analogues) with the assistance of computational analyses to support the precision design and screening of anti-SARS-CoV-2 drugs.

Oral Methioninase for Covid-19 Methionine-restriction Therapy.

The Covid-19 pandemic is a world-wide crisis without an effective therapy. While most approaches to therapy are using repurposed drugs that were developed for other diseases, it is thought that targeting the biology of the SARS-CoV-2 virus, which causes Covid-19, can result in an effective therapeutic treatment. The coronavirus RNA cap structure is methylated by two viral methyltransferases that transfer methyl groups from S-adenosylmethionine (SAM). The proper methylation of the virus depends on the level of methionine in the host to form SAM. Herein, we propose to restrict methionine availability by treating the patient with oral recombinant methioninase, aiming to treat Covid-19. By restricting methionine we not only interdict viral replication, which depends on the viral RNA cap methyaltion, but also inhibit the proliferation of the infected cells, which have an increased requirement for methionine. Most importantly, the virally-induced T-cell- and macrophage-mediated cytokine storm, which seems to be a significant cause for Covid-19 deaths, can also be inhibited by restricting methionine, since T-cell and macrophrage activation greatly increases the methionine requirement for these cells. The evidence reviewed here suggests that oral recombinant methioninase could be a promising treatment for coronavirus patients.