Amphiphilic Heparinoids as Potent Antiviral Agents against SARS-CoV-2.

Herein, we report the synthesis and biological evaluation of a novel series of heparinoid amphiphiles as inhibitors of heparanase and SARS-CoV-2. By employing a tailor-made synthetic strategy, a library of highly sulfated homo-oligosaccharides bearing d-glucose or a C5-epimer (i.e.

Sequence- and Structure-Dependent Cytotoxicity of Phosphorothioate and 2'--Methyl Modified Single-Stranded Oligonucleotides.

Single-stranded oligonucleotides (SSOs) are a rapidly expanding class of therapeutics that comprises antisense oligonucleotides, microRNAs, and aptamers, with ten clinically approved molecules. Chemical modifications such as the phosphorothioate backbone and the 2'--methyl ribose can improve the stability and pharmacokinetic properties of therapeutic SSOs, but they can also lead to toxicity and through nonspecific interactions with cellular proteins, gene expression changes, disturbed RNA processing, and changes in nuclear structures and protein distribution. In this study, we screened a mini library of 277 phosphorothioate and 2'--methyl-modified SSOs, with or without mRNA complementarity, for cytotoxic properties in two cancer cell lines.

Characterization of Posttranslationally Modified PHF-1 Tau Peptides Using Gaussian Accelerated Molecular Dynamics Simulation.

The microtubule-associated protein, Tau, is an intrinsically disordered protein that plays a crucial role in neurodegenerative diseases like Alzheimer's disease. The posttranslational modifications across the Tau protein domains are involved in regulating Tau protein's function and disease onset. Of the various posttranslational modifications at Ser, Thr, and Tyr sites, O-GlcNAcylation and phosphorylation are the most critical ones, playing a vital role in Tau aggregation and tauopathies.

Targeting the hSSB1-INTS3 Interface: A Computational Screening Driven Approach to Identify Potential Modulators.

Human single-stranded DNA binding protein 1 (hSSB1) forms a heterotrimeric complex, known as a sensor of single-stranded DNA binding protein 1 (SOSS1), in conjunction with integrator complex subunit 3 (INTS3) and C9ORF80. This sensory protein plays an important role in homologous recombination repair of double-strand breaks in DNA to efficiently recruit other repair proteins at the damaged sites. Previous studies have identified elevated hSSB1-mediated DNA repair activities in various cancers, highlighting its potential as an anticancer target.

Structural and mechanistic characterization of bifunctional heparan sulfate N-deacetylase-N-sulfotransferase 1.

Heparan sulfate (HS) polysaccharides are major constituents of the extracellular matrix, which are involved in myriad structural and signaling processes. Mature HS polysaccharides contain complex, non-templated patterns of sulfation and epimerization, which mediate interactions with diverse protein partners. Complex HS modifications form around initial clusters of glucosamine-N-sulfate (GlcNS) on nascent polysaccharide chains, but the mechanistic basis underpinning incorporation of GlcNS itself into HS remains unclear.

analysis of crustacean hyperglycemic hormone family G protein-coupled receptor candidates.

Ecdysteroid molting hormone synthesis is directed by a pair of molting glands or Y-organs (YOs), and this synthesis is inhibited by molt-inhibiting hormone (MIH). MIH is a member of the crustacean hyperglycemic hormone (CHH) neuropeptide superfamily, which includes CHH and insect ion transport peptide (ITP). It is hypothesized that the MIH receptor is a Class A (Rhodopsin-like) G protein-coupled receptor (GPCR).

An Exploration of Small Molecules That Bind Human Single-Stranded DNA Binding Protein 1.

Human single-stranded DNA binding protein 1 (hSSB1) is critical to preserving genome stability, interacting with single-stranded DNA (ssDNA) through an oligonucleotide/oligosaccharide binding-fold. The depletion of hSSB1 in cell-line models leads to aberrant DNA repair and increased sensitivity to irradiation. hSSB1 is over-expressed in several types of cancers, suggesting that hSSB1 could be a novel therapeutic target in malignant disease.

Targeting the COMMD4-H2B protein complex in lung cancer.

Background: Lung cancer is the biggest cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 85-90% of all lung cancers. Identification of novel therapeutic targets are required as drug resistance impairs chemotherapy effectiveness.

Dynamics and recognition of homeodomain containing protein-DNA complex of IRX4.

Iroquois Homeobox 4 (IRX4) belongs to a family of homeobox TFs having roles in embryogenesis, cell specification, and organ development. Recently, large scale genome-wide association studies and epigenetic studies have highlighted the role of IRX4 and its associated variants in prostate cancer. No studies have investigated and characterized the structural aspect of the IRX4 homeodomain and its potential to bind to DNA.

Comparative Assessment of Docking Programs for Docking and Virtual Screening of Ribosomal Oxazolidinone Antibacterial Agents.

Oxazolidinones are a broad-spectrum class of synthetic antibiotics that bind to the 50S ribosomal subunit of Gram-positive and Gram-negative bacteria. Many crystal structures of the ribosomes with oxazolidinone ligands have been reported in the literature, facilitating structure-based design using methods such as molecular docking. It would be of great interest to know in advance how well docking methods can reproduce the correct ligand binding modes and rank these correctly.

Integration of molecular modelling and studies to inhibit LexA proteolysis.

Introduction: As antibiotic resistance has become more prevalent, the social and economic impacts are increasingly pressing. Indeed, bacteria have developed the SOS response which facilitates the evolution of resistance under genotoxic stress. The transcriptional repressor, LexA, plays a key role in this response.

Integrative competing endogenous RNA network analyses identify novel lncRNA and genes implicated in metastatic breast cancer.

Competing endogenous RNAs (ceRNAs) have gained attention in cancer research owing to their involvement in microRNA-mediated gene regulation. Previous studies have identified ceRNA networks of individual cancers. Nevertheless, none of these studies has investigated different cancer stages.

Structural investigation of CDCA3-Cdh1 protein-protein interactions using in vitro studies and molecular dynamics simulation.

The anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase and its cofactor, Cdh1, regulate the expression of several cell-cycle proteins and their functions during mitosis. Levels of the protein cell division cycle-associated protein 3 (CDCA3), which is functionally required for mitotic entry, are regulated by APC/C . CDCA3 is an intrinsically disordered protein and contains both C-terminal KEN box and D-box recognition motifs, enabling binding to Cdh1.

Evidence for Multiple Binding Modes in the Initial Contact Between SARS-CoV-2 Spike S1 Protein and Cell Surface Glycans.

Infection of host cells by SARS-CoV-2 begins with recognition by the virus S (spike) protein of cell surface heparan sulfate (HS), tethering the virus to the extracellular matrix environment, and causing the subunit S1-RBD to undergo a conformational change into the 'open' conformation. These two events promote the binding of S1-RBD to the angiotensin converting enzyme 2 (ACE2) receptor, a preliminary step toward viral-cell membrane fusion. Combining ligand-based NMR spectroscopy with molecular dynamics, oligosaccharide analogues were used to explore the interactions between S1-RBD of SARS CoV-2 and HS, revealing several low-specificity binding modes and previously unidentified potential sites for the binding of extended HS polysaccharide chains.

Dehydroepiandrosterone Sulfate and Colorectal Cancer Risk: A Mendelian Randomization Analysis.

Colorectal cancer is the third most common and second most deadly type of cancer worldwide, with approximately 1.9 million cases and 0.9 million deaths worldwide in 2020.

Molecular basis of transport of surface functionalised gold nanoparticles to pulmonary surfactant.

Ligands like alkanethiol ( dodecanethiol, hexadecanethiol, ) and polymers ( poly(vinyl pyrrolidone), polyethylene glycol-thiol) capped to the gold nanoparticles (AuNPs) are widely used in biomedical field as drug carriers and as promising materials for probing and manipulating cellular processes. Ligand functionalised AuNPs are known to interact with the pulmonary surfactant (PS) monolayer once reaching the alveolar region. Therefore, it is crucial to understand the interaction between AuNPs and PS monolayers.

A supervised machine learning approach identifies gene-regulating factor-mediated competing endogenous RNA networks in hormone-dependent cancers.

Competing endogenous RNAs (ceRNAs) have become an emerging topic in cancer research due to their role in gene regulatory networks. To date, traditional ceRNA bioinformatic studies have investigated microRNAs as the only factor regulating gene expression. Growing evidence suggests that genomic (e.

Structural Insights into Pixatimod (PG545) Inhibition of Heparanase, a Key Enzyme in Cancer and Viral Infections.

Pixatimod (PG545), a heparan sulfate (HS) mimetic and anticancer agent currently in clinical trials, is a potent inhibitor of heparanase. Heparanase is an endo-β-glucuronidase that degrades HS in the extracellular matrix and basement membranes and is implicated in numerous pathological processes such as cancer and viral infections, including SARS-CoV-2. To understand how PG545 interacts with heparanase, we firstly carried out a conformational analysis through a combination of NMR experiments and molecular modelling which showed that the reducing end β-D-glucose residue of PG545 adopts a distorted conformation.

The Impact of Rare Human Variants on Barrier-To-Auto-Integration Factor 1 (Banf1) Structure and Function.

Barrier-to-Autointegration Factor 1 (Banf1/BAF) is a critical component of the nuclear envelope and is involved in the maintenance of chromatin structure and genome stability. Banf1 is a small DNA binding protein that is conserved amongst multicellular eukaryotes. Banf1 functions as a dimer, and binds non-specifically to the phosphate backbone of DNA, compacting the DNA in a looping process.

Identifying Complex lncRNA/Pseudogene-miRNA-mRNA Crosstalk in Hormone-Dependent Cancers.

The discovery of microRNAs (miRNAs) has fundamentally transformed our understanding of gene regulation. The competing endogenous RNA (ceRNA) hypothesis postulates that messenger RNAs and other RNA transcripts, such as long non-coding RNAs and pseudogenes, can act as natural miRNA sponges. These RNAs influence each other's expression levels by competing for the same pool of miRNAs through miRNA response elements on their target transcripts, thereby modulating gene expression and protein activity.

Integrative Transcriptome-Wide Analyses Uncover Novel Risk-Associated MicroRNAs in Hormone-Dependent Cancers.

Background: Hormone-dependent cancers (HDC) are among the leading causes of death worldwide among both men and women. Some of the established risk factors of HDC include unhealthy lifestyles, environmental factors, and genetic influences. Numerous studies have been conducted to understand gene-cancer associations.

Design and Characterization of a Cell-Penetrating Peptide Derived from the SOX2 Transcription Factor.

SOX2 is an oncogenic transcription factor overexpressed in nearly half of the basal-like triple-negative breast cancers associated with very poor outcomes. Targeting and inhibiting SOX2 is clinically relevant as high SOX2 mRNA levels are positively correlated with decreased overall survival and progression-free survival in patients affected with breast cancer. Given its key role as a master regulator of cell proliferation, SOX2 represents an important scaffold for the engineering of dominant-negative synthetic DNA-binding domains (DBDs) that act by blocking or interfering with the oncogenic activity of the endogenous transcription factor in cancer cells.

Phosphorylation and -GlcNAcylation of the PHF-1 Epitope of Tau Protein Induce Local Conformational Changes of the C-Terminus and Modulate Tau Self-Assembly Into Fibrillar Aggregates.

Phosphorylation of the neuronal microtubule-associated Tau protein plays a critical role in the aggregation process leading to the formation of insoluble intraneuronal fibrils within Alzheimer's disease (AD) brains. In recent years, other posttranslational modifications (PTMs) have been highlighted in the regulation of Tau (dys)functions. Among these PTMs, the -β-linked N-acetylglucosaminylation (-GlcNAcylation) modulates Tau phosphorylation and aggregation.

From Cancer to COVID-19: A Perspective on Targeting Heparan Sulfate-Protein Interactions.

Heparan sulfate (HS) is a complex, polyanionic polysaccharide ubiquitously expressed on cell surfaces and in the extracellular matrix. HS interacts with numerous proteins to mediate a vast array of biological and pathological processes. Inhibition of HS-protein interactions is thus an attractive approach for new therapeutic development for cancer and infectious diseases, including COVID-19; however, synthesis of well-defined native HS oligosaccharides remains challenging.