SARS-CoV-2 replication and drug discovery.

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed millions of people and continues to wreak havoc across the globe. This sudden and deadly pandemic emphasizes the necessity for anti-viral drug development that can be rapidly administered to reduce morbidity, mortality, and virus propagation. Thus, lacking efficient anti-COVID-19 treatment, and especially given the lengthy drug development process as well as the critical death tool that has been associated with SARS-CoV-2 since its outbreak, drug repurposing (or repositioning) constitutes so far, the ideal and ready-to-go best approach in mitigating viral spread, containing the infection, and reducing the COVID-19-associated death rate. Indeed, based on the molecular similarity approach of SARS-CoV-2 with previous coronaviruses (CoVs), repurposed drugs have been reported to hamper SARS-CoV-2 replication. Therefore, understanding the inhibition mechanisms of viral replication by repurposed anti-viral drugs and chemicals known to block CoV and SARS-CoV-2 multiplication is crucial, and it opens the way for particular treatment options and COVID-19 therapeutics. In this review, we highlighted molecular basics underlying drug-repurposing strategies against SARS-CoV-2. Notably, we discussed inhibition mechanisms of viral replication, involving and including inhibition of SARS-CoV-2 proteases (3C-like protease, 3CLpro or Papain-like protease, PLpro) by protease inhibitors such as Carmofur, Ebselen, and GRL017, polymerases (RNA-dependent RNA-polymerase, RdRp) by drugs like Suramin, Remdesivir, or Favipiravir, and proteins/peptides inhibiting virus-cell fusion and host cell replication pathways, such as Disulfiram, GC376, and Molnupiravir. When applicable, comparisons with SARS-CoV inhibitors approved for clinical use were made to provide further insights to understand molecular basics in inhibiting SARS-CoV-2 replication and draw conclusions for future drug discovery research.

Genetic Diversity and Functional Analysis of Sigma Factors in Enterobacter cloacae Complex Resourced From Various Niche.

Sigma factors are bacterial transcription factors that bind the core RNA polymerase and direct transcription initiation at a specific promoter site. These specialized sigma factors bind the promoters of genes appropriate to the environmental conditions and selectively increase the transcription of those genes. Here, we attempt to identify sigma factors in 5 genomes belonging to the Enterobacter cloacae complex (Ecc), a group of gram-negative bacteria that are important nosocomial pathogens. This process includes the identification of orthologous sequences, conserved motifs, domains, families, phylogenetic profiles, and protein-protein associations of these components. Based on the reference genome, genome-wide comparison revealed that the genomes of Enterobacter asburiae JCM6051, Enterobacter nimipressuralis CIP 104980, Enterobacter hormaechei ATCC49162, Enterobacter kobei JCM 8580, and Enterobacter ludwigii EN-119 encode 10 sigma factors that exist in the reference strain Enterobacter cloacae subsp cloacae ATCC13047. Moreover, the sequence similarity, protein domains and families of the sigma factors, protein-protein association, and phylogenetic profile indicate that the sigma factor proteins of these 5 strains may have evolutionary relatedness and functional characteristics important to their various environmental niches. Interestingly, the absence of RpoS in E kobei, which contributes to bacterial survival under environmental stress conditions, indicates that RpoS might have been independently acquired and may play different roles relating to pathogenicity, host range determination, and/or niche adaptation. Future work such as RNA sequencing will be directed towards investigating the roles that these sigma factors play in the biology of the Ecc.