Computational screening combined with well-tempered metadynamics simulations identifies potential TMPRSS2 inhibitors.

Type-II transmembrane serine proteases are effective pharmacological targets for host defence against viral entry and in certain cancer cell progressions. These serine proteases cleave viral spike proteins to expose the fusion peptide for cell entry, which is essential to the life cycle of the virus. TMPRSS2 inhibitors can also fight against respiratory viruses that employ them for cell entry.

Discovery of small molecule entry inhibitors targeting the linoleic acid binding pocket of SARS-CoV-2 spike protein.

Spike glycoprotein has a significant role in the entry of SARS-CoV-2 to host cells, which makes it a potential drug target. Continued accumulation of non-synonymous mutations in the receptor binding domain of spike protein poses great challenges in identifying antiviral drugs targeting this protein. This study aims to identify potential entry inhibitors of SARS-CoV-2 using virtual screening and molecular dynamics (MD) simulations from three distinct chemical libraries including Pandemic Response Box, Drugbank and DrugCentral, comprising 6971 small molecules.

A high-throughput screening system for SARS-CoV-2 entry inhibition, syncytia formation and cell toxicity.

Background: The entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the host cell is mediated through the binding of the SARS-CoV-2 Spike protein via the receptor binding domain (RBD) to human angiotensin-converting enzyme 2 (hACE2). Identifying compounds that inhibit Spike-ACE2 binding would be a promising and safe antiviral approach against COVID-19.

Methods: In this study, we used a BSL-2 compatible replication-competent vesicular stomatitis virus (VSV) expressing Spike protein of SARS-CoV-2 with eGFP reporter system (VSV-eGFP-SARS-CoV-2) in a recombinant permissive cell system for high-throughput screening of viral entry blockers.

Search for novel ATP4 inhibitors from the MMV Pandemic Response Box through a virtual screening approach.

Owing to its life cycle involving multiple hosts and species-specific biological complexities, a vaccine against , the causative agent of remains elusive. This makes chemotherapy the only viable means to address the clinical manifestations and spread of this deadly disease. However, rapid surge in antimalarial resistance poses significant challenges to our efforts to eliminate since the best drug available to-date; Artemisinin and its combinations are also rapidly losing efficacy.

In vitro antibacterial effects of combination of ciprofloxacin with compounds isolated from Streptomyces luteireticuli NIIST-D75.

Three phenazines, 1-methoxyphenazine (1), methyl-6-methoxyphenazine-1-carboxylate (2), 1,6-dimethoxyphenazine (4), and a 2,3-dimethoxy benzamide (3) were isolated from the Streptomyces luteireticuli NIIST-D75, and the antibacterial effects of compounds 1-3, each in combination with ciprofloxacin, were investigated. The in vitro antibacterial activity was assessed by microdilution, checkerboard, and time-kill assay against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Salmonella typhi. According to the checkerboard assay results, each combination of compounds 1, 2 and 3 with ciprofloxacin resulted in a significantly lower minimum inhibitory concentrations (MICs) of 0.

Genomic insight into the environmental adaptations and toxigenic features of endophytic CaB1 isolated from L.

Unlabelled: In the study, a previously isolated plant beneficial endophytic CaB1 was selected for the detailed analysis by whole-genome sequencing. The WGS has generated a total of 1.9 GB high-quality data which was assembled into a 5,257,162 bp genome with G + C content of 35.

Hybrid genome assembly and annotation of multidrug-resistant Staphylococcus aureus genotype ST672-SCCmec type IVd (2B).

Objectives: The emergence of multidrug-resistant Staphylococcus aureus strains is mainly mediated by mobile genetic elements, such as Staphylococcal Cassette Chromosome mec (SCCmec). Currently, SCCmec elements in S. aureus are classified into 15 types, with type IV being the most common in hospital and community-associated methicillin-resistant S.

study identifies peptide inhibitors that negate the effect of non-synonymous mutations in major drug targets of SARS-CoV-2 variants.

Since its advent in December 2019, SARS-CoV-2 has diverged into multiple variants with differing levels of virulence owing to the accumulation of mutations in its genome. The structural changes induced by non-synonymous mutations in major drug targets of the virus are known to alter the binding of potential antagonistic inhibitors. Here, we analyzed the effects of non-synonymous mutations in major targets of SARS-CoV-2 in response to potential peptide inhibitors.

A rapid bead-based assay for screening of SARS-CoV-2 neutralizing antibodies.

Quantitative determination of neutralizing antibodies against Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) is paramount in immunodiagnostics, vaccine efficacy testing, and immune response profiling among the vaccinated population. Cost-effective, rapid, easy-to-perform assays are essential to support the vaccine development process and immunosurveillance studies. We describe a bead-based screening assay for S1-neutralization using recombinant fluorescent proteins of hACE2 and SARS-CoV2-S1, immobilized on solid beads employing nanobodies/metal-affinity tags.

Mutational landscape and in silico structure models of SARS-CoV-2 spike receptor binding domain reveal key molecular determinants for virus-host interaction.

Background: SARS-CoV-2, the causative agent of COVID-19 pandemic is a RNA virus prone to mutations. Formation of a stable binding interface between the Receptor Binding Domain (RBD) of SARS-CoV-2 Spike (S) protein and Angiotensin-Converting Enzyme 2 (ACE2) of host is pivotal for viral entry. RBD has been shown to mutate frequently during pandemic.

SSTP1, a Host Defense Peptide, Exploits the Immunomodulatory IL6 Pathway to Induce Apoptosis in Cancer Cells.

While the immunomodulatory pathways initiated in immune cells contribute to therapeutic response, their activation in cancer cells play a role in cancer progression. Also, many of the aberrantly expressed immunomodulators on cancer cells are considered as therapeutic targets. Here, we introduce host defense peptide (HDP), a known immuomodulator, as a therapeutic agent to target them.

Anomalous Phylogenetic Behavior of Ribosomal Proteins in Metagenome-Assembled Asgard Archaea.

Metagenomic studies permit the exploration of microbial diversity in a defined habitat, and binning procedures enable phylogenomic analyses, taxon description, and even phenotypic characterizations in the absence of morphological evidence. Such lineages include asgard archaea, which were initially reported to represent archaea with eukaryotic cell complexity, although the first images of such an archaeon show simple cells with prokaryotic characteristics. However, these metagenome-assembled genomes (MAGs) might suffer from data quality problems not encountered in sequences from cultured organisms due to two common analytical procedures of bioinformatics: assembly of metagenomic sequences and binning of assembled sequences on the basis of innate sequence properties and abundance across samples.

Pax6 modulates intra-retinal axon guidance and fasciculation of retinal ganglion cells during retinogenesis.

Intra-retinal axon guidance involves a coordinated expression of transcription factors, axon guidance genes, and secretory molecules within the retina. Pax6, the master regulator gene, has a spatio-temporal expression typically restricted till neurogenesis and fate-specification. However, our observation of persistent expression of Pax6 in mature RGCs led us to hypothesize that Pax6 could play a major role in axon guidance after fate specification.

Insights into the Bacterial Profiles and Resistome Structures Following the Severe 2018 Flood in Kerala, South India.

Extreme flooding is one of the major risk factors for human health, and it can significantly influence the microbial communities and enhance the mobility of infectious disease agents within the affected areas. The flood crisis in 2018 was one of the severe natural calamities recorded in the southern state of India (Kerala) that significantly affected its economy and ecological habitat. We utilized a combination of shotgun metagenomics and bioinformatics approaches to understand the bacterial profile and the abundance of pathogenic and antibiotic-resistant bacteria in extremely flooded areas of Kuttanad, Kerala (4-10 feet below sea level).

Evolutionary, genetic, structural characterization and its functional implications for the influenza A (H1N1) infection outbreak in India from 2009 to 2017.

Influenza A (H1N1) continues to be a major public health threat due to possible emergence of a more virulent H1N1 strain resulting from dynamic changes in virus adaptability consequent to functional mutations and antigenic drift in the hemagglutinin (HA) and neuraminidase (NA) surface proteins. In this study, we describe the genetic and evolutionary characteristics of H1N1 strains that circulated in India over a period of nine years from 2009 to 2017 in relation to global strains. The finding is important from a global perspective since previous phylogenetic studies have suggested that the tropics contributed substantially to the global circulation of influenza viruses.

Phylogenomic Analysis Reveals the Evolutionary Route of Resistant Genes in Staphylococcus aureus.

Multidrug-resistant Staphylococcus aureus is a leading concern worldwide. Coagulase-Negative Staphylococci are claimed to be the reservoir and source of important resistant elements in S. aureus.

Genomic perspective of triazole resistance in clinical and environmental Aspergillus fumigatus isolates without cyp51A mutations.

Aspergillus fumigatus is the most common etiologic agent of primarily all clinical manifestations of aspergillosis. A steady increase in the number of azole resistant A. fumigatus (ARAF) isolates from environment and clinical samples leading to therapeutic failures in clinical settings have alarmed the mycologists and clinicians worldwide.

Failure to Recover Major Events of Gene Flux in Real Biological Data Due to Method Misapplication.

In prokaryotes, known mechanisms of lateral gene transfer (transformation, transduction, conjugation, and gene transfer agents) generate new combinations of genes among chromosomes during evolution. In eukaryotes, whose host lineage is descended from archaea, lateral gene transfer from organelles to the nucleus occurs at endosymbiotic events. Recent genome analyses studying gene distributions have uncovered evidence for sporadic, discontinuous events of gene transfer from bacteria to archaea during evolution.

Physiology, phylogeny, and LUCA.

Genomes record their own history. But if we want to look all the way back to life's beginnings some 4 billion years ago, the record of microbial evolution that is preserved in prokaryotic genomes is not easy to read. Microbiology has a lot in common with geology in that regard.

Late Mitochondrial Origin Is an Artifact.

The origin of mitochondria was a crucial event in eukaryote evolution. A recent report claimed to provide evidence, based on branch length variation in phylogenetic trees, that the mitochondrion came late in eukaryotic evolution. Here, we reinvestigate their claim with a reanalysis of the published data.

The physiology and habitat of the last universal common ancestor.

The concept of a last universal common ancestor of all cells (LUCA, or the progenote) is central to the study of early evolution and life's origin, yet information about how and where LUCA lived is lacking. We investigated all clusters and phylogenetic trees for 6.1 million protein coding genes from sequenced prokaryotic genomes in order to reconstruct the microbial ecology of LUCA.

One step beyond a ribosome: The ancient anaerobic core.

Life arose in a world without oxygen and the first organisms were anaerobes. Here we investigate the gene repertoire of the prokaryote common ancestor, estimating which genes it contained and to which lineages of modern prokaryotes it was most similar in terms of gene content. Using a phylogenetic approach we found that among trees for all 8779 protein families shared between 134 archaea and 1847 bacterial genomes, only 1045 have sequences from at least two bacterial and two archaeal groups and retain the ancestral archaeal-bacterial split.

The Origin of a Killer Revealed by Bronze Age Yersinia Genomes.

Bubonic plaque is caused by Yersinia pestis, a deadly pathogen that left deep scars in human history. Rasmussen et al. (2015) have now retrieved Y.