Unraveling the molecular basis for G-quadruplex-binders to ALS/FTD-associated G4C2 repeats of the C9orf72 gene.

The most recurrent familial cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the presence of an abnormal number of intronic GGGGCC (G4C2) repetitions in the C9orf72 gene, which has been proposed to drive ALS/FTD pathogenesis. Recently, it has been shown that such G4C2 repetitions can fold into G-quadruplex (G4) secondary structures. These G4s have been selectively stabilized by small-molecule binders, furnishing proof of principle that targeting these non-canonical nucleic acid sequences represents a novel and effective therapeutic strategy to tackle neurodegenerative disorders.

Design of a Solution-Gated Graphene Transistor Sensor for the Efficient Detection of Guanine Quadruplexes.

Guanine quadruplexes (G4s) are nucleic acid structures present in diverse regions of the genome, such as telomeres and transcription initiators. Recently, the different biological roles of G4s have been evidenced as well as their role as biomarkers for tumors or viral infections. However, the fast and efficient detection of G4s in complex matrices remains elusive.

Resolving the Structure of a Guanine Quadruplex in TMPRSS2 Messenger RNA by Circular Dichroism and Molecular Modeling.

The presence of a guanine quadruplex in the opening reading frame of the messenger RNA coding for the transmembrane serine protease 2 (TMPRSS2) may pave the way to original anticancer and host-oriented antiviral strategy. Indeed, TMPRSS2 in addition to being overexpressed in different cancer types, is also related to the infection of respiratory viruses, including SARS-CoV-2, by promoting the cellular and viral membrane fusion through its proteolytic activity. The design of selective ligands targeting TMPRSS2 messenger RNA requires a detailed knowledge, at atomic level, of its structure.

How the Metal Ion Affects the H NMR Chemical Shift Values of Schiff Base Metal Complexes: Rationalization by DFT Calculations.

The chemical shift (CS) values obtained by H NMR spectroscopy for the hydrogen atoms of a tetradentate NO-substituted Salphen ligand (H) are differently shifted in its complexes of nickel(II), palladium(II), platinum(II), and zinc(II), all bearing the same charge on the metal ions. To rationalize the observed trends, DFT calculations have been performed in the implicit -DMSO solvent in terms of the electronic effects induced by the metal ion and of the nature and strength of the metal-N and metal-O bonds. Overall, the results obtained point out that, in the complexes involving group 10 elements, the CS values show the greater shift when considering the two hydrogen atoms at a shorter distance from the coordinated metal center and follow the decreasing metal charge in the order Ni > Pd > Pt.

Resolving a guanine-quadruplex structure in the SARS-CoV-2 genome through circular dichroism and multiscale molecular modeling.

The genome of SARS-CoV-2 coronavirus is made up of a single-stranded RNA fragment that can assume a specific secondary structure, whose stability can influence the virus's ability to reproduce. Recent studies have identified putative guanine quadruplex sequences in SARS-CoV-2 genome fragments that are involved in coding for both structural and non-structural proteins. In this contribution, we focus on a specific G-rich sequence referred to as RG-2, which codes for the non-structural protein 10 (Nsp10) and assumes a guanine-quadruplex (G4) arrangement.

Mechanism of the Covalent Inhibition of Human Transmembrane Protease Serine 2 as an Original Antiviral Strategy.

The Transmembrane Protease Serine 2 (TMPRSS2) is a human enzyme which is involved in the maturation and post-translation of different proteins. In addition to being overexpressed in cancer cells, TMPRSS2 plays a further fundamental role in favoring viral infections by allowing the fusion of the virus envelope with the cellular membrane, notably in SARS-CoV-2. In this contribution, we resort to multiscale molecular modeling to unravel the structural and dynamical features of TMPRSS2 and its interaction with a model lipid bilayer.

Predicting the Three-Dimensional Structure of the c- Proto-Oncogene Promoter and the Dynamics of Its Strongly Coupled Guanine Quadruplexes.

Guanine quadruplexes (G4s) play essential protective and regulatory roles within cells, influencing gene expression. In several gene-promoter regions, multiple G4-forming sequences are in close proximity and may form three-dimensional arrangements. We analyze the interplay among the three neighboring G4s in the c- proto-oncogene promoter (WK1, WSP, and WK2).

Understanding the Interactions of Guanine Quadruplexes with Peptides as Novel Strategies for Diagnosis or Tuning Biological Functions.

Guanine quadruplexes (G4s) are nucleic acid structures exhibiting a complex structural behavior and exerting crucial biological functions in both cells and viruses. The specific interactions of peptides with G4s, as well as an understanding of the factors driving the specific recognition are important for the rational design of both therapeutic and diagnostic agents. In this review, we examine the most important studies dealing with the interactions between G4s and peptides, highlighting the strengths and limitations of current analytic approaches.

Salphen metal complexes as potential anticancer agents: interaction profile and selectivity studies toward the three G-quadruplex units in the promoter.

DNA G-rich sequences can organize in four-stranded structures called G-quadruplexes (G4s). These motifs are enriched in significant sites within the human genomes, including telomeres and promoters of cancer related genes. For instance, proto-oncogene promoter, associated with diverse cancers, contains three adjacent G4 units, namely Kit2, SP, and Kit1.