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.

Glioblastoma Cell Migration, Invasion and Vasculogenic Mimicry Downmodulated by Novel uPAcyclin Derivatives.

Despite extensive efforts to develop new treatments, the prognosis for glioblastoma multiforme (GBM) is extremely unfavorable, urging the identification of new chemotherapeutics. A previous work identified the cyclic decapeptide uPAcyclin as a potent inhibitor of GBM cell migration, matrix invasion and vascular-like structures' formation, acting through binding to αV integrins and not interfering with cell proliferation or survival. These clearcut activities prompted us to design and test novel derivatives on cultured U87-MG and U251 GBM-MG human cells.

Sustainable Ultrasound-Assisted Solid-Phase peptide synthesis (SUS-SPPS): Less Waste, more efficiency.

The integration of low-frequency ultrasound with Solid-Phase Peptide Synthesis (SPPS) was explored to establish a Sustainable Ultrasound-assisted Solid-Phase Peptide Synthesis (SUS-SPPS) method. This innovative approach significantly reduces solvent consumption, washing steps, time, and reagent usage compared to conventional manual SPPS protocols. The SUS-SPPS method exploits ultrasound at every stage of synthesis and work-up, reducing the process to just two steps.

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.

Comprehensive structural investigation of a potent and selective CXCR4 antagonist via crosslink modification.

Macrocyclization presents a valuable strategy for enhancing the pharmacokinetic and pharmacodynamic profiles of short bioactive peptides. The exploration of various macrocyclic characteristics, such as crosslinking tethers, ring size, and orientation, is generally conducted during the early stages of development. Herein, starting from a potent and selective C-X-C chemokine receptor 4 (CXCR4) cyclic heptapeptide antagonist mimicking the N-terminal region of CXCL12, we demonstrated that the disulfide bridge could be successfully replaced with a side-chain to side-chain lactam bond, which is commonly not enlisted among the conventional disulfide mimetics.

Expanding Structure-Activity Relationships of Human Urotensin II Peptide Analogues: A Proposed Key Role of the N-Terminal Region for Novel Urotensin II Receptor Modulators.

While the urotensinergic system plays a role in influencing various pathologies, its potential remains untapped because of the absence of therapeutically effective urotensin II receptor (UTR) modulators. Herein, we developed analogues of human urotensin II () peptide in which, along with well-known antagonist-oriented modifications, the Glu residue was subjected to single-point mutations. The generated library was tested by a calcium mobilization assay and ex vivo experiments, also in competition with selected ligands.

Disulfide bond replacement with non-reducible side chain to tail macrolactamization for the development of potent and selective CXCR4 peptide antagonists endowed with flanking binding sites.

The present study describes a small library of peptides derived from a potent and selective CXCR4 antagonist (3), wherein the native disulfide bond is replaced using a side-chain to tail macrolactamization technique to vary ring size and amino acid composition. The peptides were preliminary assessed for their ability to interfere with the interaction between the receptor and anti-CXCR4 PE-conjugated antibody clone 12G5. Two promising candidates (13 and 17) were identified and further evaluated in aI-CXCL12 competition binding assay, exhibiting IC in the low-nanomolar range.

Strategic Single-Residue Substitution in the Antimicrobial Peptide Esc(1-21) Confers Activity against , Including Drug-Resistant and Biofilm Phenotype.

, a bacterium resistant to multiple drugs, is a significant cause of illness and death worldwide. Antimicrobial peptides (AMPs) provide an excellent potential strategy to cope with this threat. Recently, we characterized a derivative of the frog-skin AMP esculentin-1a, Esc(1-21) () that is endowed with potent activity against Gram-negative bacteria but poor efficacy against Gram-positive strains.

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.

Development and Nanoparticle-Mediated Delivery of Novel MDM2/MDM4 Heterodimer Peptide Inhibitors to Enhance 5-Fluorouracil Nucleolar Stress in Colorectal Cancer Cells.

Colorectal cancer (CRC) often involves wild-type p53 inactivation by MDM2 and MDM4 overexpression, promoting tumor progression and resistance to 5-fluoruracil (5-FU). Disrupting the MDM2/4 heterodimer can proficiently reactivate p53, sensitizing cancer cells to 5-FU. Herein, we developed 16 peptides based on Pep3 (), the only known peptide acting through this mechanism.

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.

New biologic (Ab-IPL-IL-17) for IL-17-mediated diseases: identification of the bioactive sequence (nIL-17) for IL-17A/F function.

Objectives: Interleukin (IL) 17s cytokines are key drivers of inflammation that are functionally dysregulated in several human immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis (RA), psoriasis and inflammatory bowel disease (IBD). Targeting these cytokines has some therapeutic benefits, but issues associated with low therapeutic efficacy and immunogenicity for subgroups of patients or IMIDs reduce their clinical use. Therefore, there is an urgent need to improve the coverage and efficacy of antibodies targeting IL-17A and/or IL-17F and IL-17A/F heterodimer.

Ultrasound-assisted Peptide Nucleic Acids synthesis (US-PNAS).

Herein, we developed an innovative and easily accessible solid-phase synthetic protocol for Peptide Nucleic Acid (PNA) oligomers by systematically investigating the ultrasonication effects in all steps of the PNA synthesis (US-PNAS). When compared with standard protocols, the application of the so-obtained US-PNAS approach succeeded in improving the crude product purities and the isolated yields of different PNA, including small or medium-sized oligomers (5-mer and 9-mer), complex purine-rich sequences (like a 5-mer Guanine homoligomer and the telomeric sequence TEL-13) and longer oligomers (such as the 18-mer anti-IVS2-654 PNA and the 23-mer anti-mRNA 155 PNA). Noteworthy, our ultrasound-assisted strategy is compatible with the commercially available PNA monomers and well-established coupling reagents and only requires the use of an ultrasonic bath, which is a simple equipment generally available in most synthetic laboratories.

The urotensin-II receptor: A marker for staging and steroid outcome prediction in ulcerative colitis.

Background: Urotensin-II receptor- (UTR) related pathway exerts a key-role in promoting inflammation. The aim was to assess the relationship between UTR expression and clinical, endoscopic and biochemical severity of ulcerative colitis (UC), exploring its predictivity of intravenous (iv) steroid administration therapeutic outcome.

Methods: One-hundred patients with first diagnosis of UC and 44 healthy subjects were enrolled.

Synthesis of temporin L hydroxamate-based peptides and evaluation of their coordination properties with iron(III ).

Ferric iron is an essential nutrient for bacterial growth. Pathogenic bacteria synthesize iron-chelating entities known as siderophores to sequestrate ferric iron from host organisms in order to colonize and replicate. The development of antimicrobial peptides (AMPs) conjugated to iron chelators represents a promising strategy for reducing the iron availability, inducing bacterial death, and enhancing simultaneously the efficacy of AMPs.

Unveiling the mechanism of action of acylated temporin L analogues against multidrug-resistant .

The increasing resistance of fungi to conventional antifungal drugs has prompted worldwide the search for new compounds. In this work, we investigated the antifungal properties of acylated Temporin L derivatives, and , against , including the multidrug-resistant strains. Acylated peptides resulted to be active both on reference and clinical strains with MIC values ranging from 6.

Synthetic Amphipathic β-Sheet Temporin-Derived Peptide with Dual Antibacterial and Anti-Inflammatory Activities.

Temporin family is one of the largest among antimicrobial peptides (AMPs), which act mainly by penetrating and disrupting the bacterial membranes. To further understand the relationship between the physical-chemical properties and their antimicrobial activity and selectivity, an analogue of Temporin L, [Nle, dLeu, dLys]TL (Nle-Phe-Val-Pro-Trp-Phe-Lys-Phe-dLeu-dLys-Arg-Ile-Leu-CONH) has been developed in the present work. The design strategy consisted of the addition of a norleucine residue at the N-terminus of the lead peptide sequence, [dLeu, dLys]TL, previously developed by our group.

Ad-hoc modifications of cyclic mimetics of SOCS1 protein: Structural and functional insights.

Suppressors of cytokine signaling 1 (SOCS1) protein, a negative regulator of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, possesses a small kinase inhibitory region (KIR) involved in the inhibition of JAK kinases. Several studies showed that mimetics of KIR-SOCS1 can be potent therapeutics in several disorders (e.g.

Broad-Spectrum Antiviral Activity of the Amphibian Antimicrobial Peptide Temporin L and Its Analogs.

The COVID-19 pandemic has evidenced the urgent need for the discovery of broad-spectrum antiviral therapies that could be deployed in the case of future emergence of novel viral threats, as well as to back up current therapeutic options in the case of drug resistance development. Most current antivirals are directed to inhibit specific viruses since these therapeutic molecules are designed to act on a specific viral target with the objective of interfering with a precise step in the replication cycle. Therefore, antimicrobial peptides (AMPs) have been identified as promising antiviral agents that could help to overcome this limitation and provide compounds able to act on more than a single viral family.

Antifungal and Antibiofilm Activity of Cyclic Temporin L Peptide Analogues against Albicans and Non-Albicans Species.

Temporins are one of the largest families of antimicrobial peptides with both anti-inflammatory and antimicrobial activity. Herein, for a panel of cyclic temporin L isoform analogues, the antifungal and antibiofilm activities were determined against representative strains, including , , , and . The outcomes indicated a significant anti-candida activity against planktonic and biofilm growth for four peptides (, , and ).

Antimicrobial Activity of a Lipidated Temporin L Analogue against Carbapenemase-Producing Clinical Isolates.

Over the years, the increasing acquisition of antibiotic resistance genes has led to the emergence of highly resistant bacterial strains and the loss of standard antibiotics' efficacy, including β-lactam/β-lactamase inhibitor combinations and the last line carbapenems. is considered one of the major exponents of a group of multidrug-resistant ESKAPE pathogens responsible for serious healthcare-associated infections. In this study, we proved the antimicrobial activity of two analogues of Temporin L against twenty carbapenemase-producing clinical isolates.

First-in-Class Cyclic Temporin L Analogue: Design, Synthesis, and Antimicrobial Assessment.

The pharmacodynamic and pharmacokinetic properties of bioactive peptides can be modulated by introducing conformational constraints such as intramolecular macrocyclizations, which can involve either the backbone and/or side chains. Herein, we aimed at increasing the α-helicity content of temporin L, an isoform of an intriguing class of linear antimicrobial peptides (AMPs), endowed with a wide antimicrobial spectrum, by the employment of diverse side-chain tethering strategies, including lactam, 1,4-substituted [1,2,3]-triazole, hydrocarbon, and disulfide linkers. Our approach resulted in a library of cyclic temporin L analogues that were biologically assessed for their antimicrobial, cytotoxic, and antibiofilm activities, leading to the development of the first-in-class cyclic peptide related to this AMP family.

Novel temporin L antimicrobial peptides: promoting self-assembling by lipidic tags to tackle superbugs.

The rapid development of antimicrobial resistance is pushing the search in the discovering of novel antimicrobial molecules to prevent and treat bacterial infections. Self-assembling antimicrobial peptides, as the lipidated peptides, are a novel and promising class of molecules capable of meeting this need. Based on previous work on Temporin L analogs, several new molecules lipidated at the N- or and the C-terminus were synthesised.