Investigating temperature-induced unfolding pathways of DNA G-quadruplexes via 2D UV resonant Raman spectroscopy.

G-quadruplexes are highly polymorphic noncanonical secondary structures of nucleic acids that play important biological roles. Understanding their unfolding mechanisms is essential for elucidating their stability and interactions. In this study, we investigated the thermal unfolding pathways of four biologically relevant G-quadruplex-forming DNA sequences using ultraviolet resonance Raman (UVRR) spectroscopy combined with advanced spectral analysis techniques.

Unveiling the biological effects of DNA G-quadruplex ligands through multi-omics data integration.

G-quadruplexes (G4s) are non-canonical DNA structures that have proved to play a pivotal role in various biological processes, including telomere maintenance and gene expression regulation. Owing to their prevalence in tumor cells, G4s have emerged as promising targets for cancer therapy, with a substantial body of research demonstrating the potential of G4 ligands as anti-cancer tools. Nonetheless, a comprehensive multi-omics study to fully elucidate the mode of action of G-quadruplex ligands is still lacking.

Identifying G-quadruplex-interacting proteins in cancer-related gene promoters.

G-quadruplexes (G4s) are noncanonical DNA or RNA secondary structures involved in numerous biological processes. Their recognition by G4-related proteins (G4RPs) is essential for modulating biological pathways, particularly those associated with transcription and cancer progression. Identifying G4RPs is crucial for understanding their role in diseases like cancer, as these proteins may represent promising therapeutic targets.

Development of linear β-turn inducers containing peptides as arc mimetics with DNA topological and sequence selectivity.

In general, biological macromolecules such as proteins interact with the major groove of the ds-DNA via hydrogen bonds formation, thus blocking the site access of TFs to specific DNA sequences. Considering that the primary sequence of arc repressor responsible for DNA binding is well-characterized as well as the 3D-conformational requisites for its optimal interactions with the specific DNA base-pairs, a series of well-tailored arc analogues could be designed using computational molecular tools and available structural data. These novel molecular entities have been synthesized following ultrasound assisted-solid phase peptide synthesis (US-SPPS), characterized by NMR experiments and screened for TAGA box selectivity on DNA oligomers using a battery of DNA displacement assays.

Phytochemical profiling, antioxidant potential, and UHPLC-HRMS analysis of Phlomis genus aerial parts for therapeutic applications.

In recent years, there has been growing interest in exploring the therapeutic potential of Phlomis species, prompting numerous scientific studies on their pharmacological properties. However, the specific therapeutic applications of Phlomis remain underexplored, warranting further investigation. Iran, as one of the primary centers of diversity for the Phlomis genus in Asia, is home to 20 species, 9 of which are endemic to the region.

Effects of hydrazone-based G-quadruplex ligands on -depleted cancer cells and a strain.

G-quadruplex (G4) DNAs are alternative nucleic acid structures, proposed to play important roles in regulating DNA replication, gene transcription, and translation. Several specialized DNA helicases are involved in cellular G4 metabolism, in some cases with redundant functions. Among them, human FANCJ/BRIP1, which has orthologs in all metazoans, is one of the most powerful G4 resolvases, believed to act mainly at DNA replication forks.

Repurposing FDA-approved drugs to target G-quadruplexes in breast cancer.

Breast cancer, a leading cause of cancer-related mortality in women, is characterized by genomic instability and aberrant gene expression, often influenced by noncanonical nucleic acid structures such as G-quadruplexes (G4s). These structures, commonly found in the promoter regions and 5'-untranslated RNA sequences of several oncogenes, play crucial roles in regulating transcription and translation. Stabilizing these G4 structures offers a promising therapeutic strategy for targeting key oncogenic pathways.

Kanamycin and G-Quadruplexes: An Exploration of Binding Interactions.

G-quadruplexes (G4s) are distinctive four-stranded nucleic acid structures formed by guanine-rich sequences, making them attractive targets for drug repurposing efforts. Modulating their stability and function holds promise for treating diseases like cancer. To identify potential drug candidates capable of interacting with these complex DNA formations, docking studies and molecular dynamics (MDs) simulations were conducted.

Expanding the Functions of KHSRP Protein: Insights into DNA G-Quadruplex Binding.

KHSRP (KH-type splicing regulatory protein) is a multifunctional nucleic acid-binding protein that regulates various cellular processes, with critical roles in controlling gene expression. G-quadruplexes (G4s) are noncanonical nucleic acid structures involved in essential cellular activities, including gene expression, and are recognized as potential therapeutic targets in cancer. The biological functions of G4s are mediated by proteins making their formation highly dynamic within cells.

Design, Synthesis, and Anticancer Activity of Drug-like Iron Chelators/G-Quadruplex Binders as Synergic Dual Targeting Agents.

Iron homeostasis is strictly related to numerous physiological pathways including cell cycle progression and cell growth. The newest anticancer strategies focus on either depleting the cells with a suitable chelator or increasing their loading by administering iron complexes to induce ferroptosis. Iron depletion inhibits cell proliferation, while iron overload induces the damage of guanine nucleobases in G-quadruplex structures via ROS generation, leading to genome instability.

Screening of native wild Salvia nemorosa populations for chemical compositions, antioxidant activity and UHPLC-HRMS profiling.

In this study, screening of the collected 70 Salvia nemorosa L. populations from 54 habitats from West Azerbaijan province, Iran was evaluated by analyzing the content of phytochemical compounds, antioxidant activity, and UHPLC-HRMS profiling in different populations. The aerial parts of the plants were analyzed based on total phenolic (TPC) and flavonoid (TFC), total tannin (TTC), ascorbic acid (AAC), chlorophylls (Cla, and Clb), total carotenoid (TCC), β-carotene, antioxidant activity (by DPPH and FRAP assays), and 40 polyphenolic compounds by UHPLC-HRMS (phenolic acids, flavonoids and fatty acyl glicosides).

Pursuing Polypharmacology: Benzothiopyranoindoles as G-Quadruplex Stabilizers and Topoisomerase I Inhibitors for Effective Anticancer Strategies.

Here, we explored the benzothiopyranoindole scaffold to develop antiproliferative agents with a polypharmacological profile targeting both G-quadruplex (G4)-structures and Topoisomerase (Topo) I enzyme. In a preliminary optimization phase, compound was selected from an in-house collection as a suitable lead for the rational development of a small library of analogs (-). When assayed in NIH's NCI-60 Human Cancer Cell Line In Vitro Screen Program, compound and its demethylated analogue showed significant antiproliferative/cytotoxic activity.

Sensitization of melanoma cells to standard chemotherapy: G-quadruplex binders as synergistic agents.

The use of chemotherapeutics has achieved considerable success in cancer therapy; however, their toxicity can severely impact patients' health. In this study, aiming to reduce the doses and potential side effects of traditional chemotherapeutics, we systematically treated A375MM human melanoma cells with seven clinically approved antineoplastic drugs, in combination with three well-characterized G-quadruplex (G4) ligands, using either simultaneous or sequential dosing schedules. Interestingly, the G4 binders synergized with most of the investigated anticancer drugs, with the degree of synergism being strictly dependent on both the treatment schedule and the drug sequence employed.

Discovering Dually Active Anti-cancer Compounds with a Hybrid AI-structure-based Approach.

Cancer's persistent growth often relies on its ability to maintain telomere length and tolerate the accumulation of DNA damage. This study explores a computational approach to identify compounds that can simultaneously target both G-quadruplex (G4) structures and poly(ADP-ribose) polymerase (PARP)1 enzyme, offering a potential multipronged attack on cancer cells. We employed a hybrid virtual screening (VS) protocol, combining the power of machine learning with traditional structure-based methods.

An unbiased lncRNA dropout CRISPR-Cas9 screen reveals RP11-350G8.5 as a novel therapeutic target for multiple myeloma.

Multiple myeloma (MM) is an incurable malignancy characterized by altered expression of coding and noncoding genes promoting tumor growth and drug resistance. Although the crucial role of long noncoding RNAs (lncRNAs) in MM is clearly established, the function of the noncoding RNAome, which might allow the design of novel therapeutics, is largely unknown. We performed an unbiased CRISPR-Cas9 loss-of-function screen of 671 lncRNAs in MM cells and their bortezomib (BZB)-resistant derivative.

Chemometrics-based analysis of the phytochemical profile and antioxidant activity of Salvia species from Iran.

In recent years, the exploration of the therapeutic potential of Salvia has gained considerable attention, leading to a growing number of scientific studies emphasizing its pharmacological properties. Despite this, therapeutic applications of Salvia remain underexploited, requiring further investigation. Iran is a major center for sage diversity in Asia, boasting 60 Salvia species, 17 of which are unique to the area.

Development of a multi-targeted chemotherapeutic approach based on G-quadruplex stabilisation and carbonic anhydrase inhibition.

A novel class of compounds designed to hit two anti-tumour targets, G-quadruplex structures and human carbonic anhydrases (hCAs) IX and XII is proposed. The induction/stabilisation of G-quadruplex structures by small molecules has emerged as an anticancer strategy, disrupting telomere maintenance and reducing oncogene expression. hCAs IX and XII are well-established anti-tumour targets, upregulated in many hypoxic tumours and contributing to metastasis.

Unlocking the potential of protein-derived peptides to target G-quadruplex DNA: from recognition to anticancer activity.

Noncanonical nucleic acid structures, particularly G-quadruplexes, have garnered significant attention as potential therapeutic targets in cancer treatment. Here, the recognition of G-quadruplex DNA by peptides derived from the Rap1 protein is explored, with the aim of developing novel peptide-based G-quadruplex ligands with enhanced selectivity and anticancer activity. Biophysical techniques were employed to assess the interaction of a peptide derived from the G-quadruplex-binding domain of the protein with various biologically relevant G-quadruplex structures.

Chemistry and Biology of Noncanonical Nucleic Acid Structures: From Physicochemical Properties to Therapeutic Applications.

The aim of this Special Issue is to highlight significant and new aspects concerning the chemistry and biology of noncanonical nucleic acid structures, with emphasis on their structure, stability, and conformational equilibria, as well as on the biological relevance of their interactions with proteins and ligands [...

Exploring the DNA-PNA heterotriplex formation in targeting the Bcl-2 gene promoter: A structural insight by physico-chemical and microsecond-scale MD investigation.

Peptide Nucleic Acids (PNAs) represent a promising tool for gene modulation in anticancer treatment. The uncharged peptidyl backbone and the resistance to chemical and enzymatic degradation make PNAs highly advantageous to form stable hybrid complexes with complementary DNA and RNA strands, providing higher stability than the corresponding natural analogues. Our and other groups' research has successfully shown that tailored PNA sequences can effectively downregulate the expression of human oncogenes using antigene, antisense, or anti-miRNA approaches.

Discovery of 2,3-Diaminoindole Derivatives as a Novel Class of NOD Antagonists.

NOD1 and NOD2 are members of the pattern recognition receptors involved in the innate immune response. Overactivation of NOD1 is implicated in inflammatory disorders, multiple sclerosis, and cancer cell metastases. NOD1 antagonists would represent valuable pharmacological tools to gain further insight into protein roles, potentially leading to new therapeutic strategies.

A combined approach of structure-based virtual screening and NMR to interrupt the PD-1/PD-L1 axis: Biphenyl-benzimidazole containing compounds as novel PD-L1 inhibitors.

Immunotherapy has emerged as a game-changing approach for cancer treatment. Although monoclonal antibodies (mAbs) targeting the programmed cell death protein 1/programmed cell death protein 1 ligand 1 (PD-1/PD-L1) axis have entered the market revolutionizing the treatment landscape of many cancer types, small molecules, although presenting several advantages including the possibility of oral administration and/or reduced costs, struggled to enter in clinical trials, suffering of water insolubility and/or inadequate potency compared with mAbs. Thus, the search for novel scaffolds for both the design of effective small molecules and possible synergistic strategies is an ongoing field of interest.

G-quadruplexes in cancer-related gene promoters: from identification to therapeutic targeting.

Introduction: Guanine-rich DNA sequences can fold into four-stranded noncanonical secondary structures called G-quadruplexes (G4s) which are widely distributed in functional regions of the human genome, such as telomeres and gene promoter regions. Compelling evidence suggests their involvement in key genome functions such as gene expression and genome stability. Notably, the abundance of G4-forming sequences near transcription start sites suggests their potential involvement in regulating oncogenes.

Screening of 20 species from Lamiaceae family based on phytochemical analysis, antioxidant activity and HPLC profiling.

The Lamiaceae family encompasses numerous species highly valued for their applications in medicine, food, and cosmetics. In order to screen the Lamiaceae family and discover new sources of phytochemicals and antioxidants, we comprehensively evaluated 20 species from this family, including Phlomis herba-venti, P. tuberosa, P.

Unveiling the interaction between DNA G-quadruplexes and RG-rich peptides.

G-quadruplexes are non-canonical DNA secondary structures formed within guanine-rich strands that play important roles in various biological processes, including gene regulation, telomere maintenance and DNA replication. The biological functions and formation of these DNA structures are strictly controlled by several proteins that bind and stabilize or resolve them. Many G-quadruplex-binding proteins feature an arginine and glycine-rich motif known as the RGG or RG-rich motif.