Current Pharmaceutical Biotechnology - Volume 26, Issue 2, 2025

Tankyrases (TNKS) are homomultimers existing in two forms, viz. TNKS1 and TNKS2. TNKS2 plays a pivotal role in carcinogenesis by activating the Wnt//β-catenin pathway. TNKS2 has been identified as a suitable target in oncology due to its crucial role in mediating tumour progression. The discovery of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl) phenyl]imidazolidine-2,4-dione, a hydantoin phenylquinazolinone derivative which exists as a racemic mixture and in its pure enantiomer forms, has reportedly exhibited inhibitory potency towards TNKS2. However, the molecular events surrounding its chirality towards TNKS2 remain unresolved.

Herein, we employed in silico methods such as molecular dynamics simulation coupled with binding free energy estimations to explore the mechanistic activity of the racemic inhibitor and its enantiomer forms on TNKS2 at a molecular level.

Favourable binding free energies were noted for all three ligands propelled by electrostatic and van der Waals forces. The positive enantiomer demonstrated the highest total binding free energy (-38.15 kcal/mol), exhibiting a more potent binding affinity to TNKS2. Amino acids PHE1035, ALA1038, and HIS1048; PHE1035, HIS1048 and ILE1039; and TYR1060, SER1033 and ILE1059 were identified as key drivers of TNKS2 inhibition for all three inhibitors, characterized by the contribution of highest residual energies and the formation of crucial high-affinity interactions with the bound inhibitors. Further assessment of chirality by the inhibitors revealed a stabilizing effect of the complex systems of all three inhibitors on the TNKS2 structure. Concerning flexibility and mobility, the racemic inhibitor and negative enantiomer revealed a more rigid structure when bound to TNKS2, which could potentiate biological activity interference. The positive enantiomer, however, displayed much more elasticity and flexibility when bound to TNKS2.

Overall, 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione and its derivatives showed their inhibitory prowess when bound to the TNKS2 target via in silico assessment. Thus, results from this study offer insight into chirality and the possibility of adjustments of the enantiomer ratio to promote greater inhibitory results. These results could also offer insight into lead optimization to enhance inhibitory effects.

Breast Cancer (BRCA) is one of the most common cancers worldwide. Abnormal Alternative Splicing (AS) is frequently observed in cancers. Understanding the intricate relationship between gene mutations and abnormal AS is vital for developing novel diagnostic and therapeutic strategies to effectively target cancer.

This study aimed to focus on the analysis of transcriptomic splicing events in patients with Breast Cancer (BRCA), particularly those with mutations in the TP53 gene. Understanding the role of AS may be helpful in revealing potential predictive indicators for survival and treatment strategies.

The splicing data were downloaded from the Cancer Genome Atlas (TCGA) breast cancer project, incorporating 972 patients in the study, classified according to TP53 mutation status. A comprehensive splicing profile of these breast tumors was outlined, and an interaction network of Alternative Splicing (AS) events and splicing factors was constructed. This allowed for the identification of specific AS events associated with TP53-mutant breast cancer. A prognostic risk model based on AS events was established, using univariate and multivariate Cox regression analyses. To understand the molecular heterogeneity, consensus clustering analyses of prognostic AS events were performed. We also investigated the association of AS patterns with the immune microenvironment and drug sensitivity.

A total of 4519 significant Alternative Splicing (AS) events were distributed among 2729 genes that were altered in TP53 mutant tumors. Based on the analysis of these events, a prognostic risk model was created involving ten AS events from ten genes (such as NKTR, CD46, VCAN, etc.). The survival analysis showed that patients with high-risk scores had significantly poorer overall survival (p<0.001, HR=2.46, 95% CI 1.90-3.18) than those with low-risk scores. Furthermore, the study identified four molecular subtypes related to AS events (C1, C2, C3, and C4), which showed significant differences in immune cell infiltration, with C1 and C4 clusters having a higher degree of immune cell infiltration than C2 and C3. The chemosensitivity analysis revealed that these different AS clusters have different sensitivities to several anticancer drugs, such as docetaxel, paclitaxel, and doxorubicin, with C1 and C4 clusters being more sensitive than the other clusters.

We have demonstrated differential transcriptomic splicing events between TP53 mutant and wild-type cases of breast cancer, establishing an effective prognostic risk model based on AS events. These findings provide new insights that may aid in understanding the biological behavior of breast cancer and potentially in optimizing treatment strategies for breast cancer.

Silene undulata is historically used for inducing vivid and prophetic lucid dreams, but limited information exists on its phytochemical composition and potential pharmacological properties.

This study aimed to investigate the phytochemical composition of S. undulata through LC-MS/MS analysis and explore its potential serotonergic activity, which could support and confirm the traditional use of S. undulata as a dream-inducing plant.

LC-MS/MS analysis was conducted on S. undulata extract, identifying 51 phytochemicals, including norharman, harmalol, harmaline, harmine, and ibogaine alkaloids. ADMET and Molecular docking investigations were employed to assess the serotonergic potential of these compounds.

The analysis revealed the presence of β-carboline alkaloids, such as norharman, harmalol, harmaline, harmine, and ibogaine, within S. undulata extract. ADMET analysis showed that these compounds have a favourable pharmacokinetic properties. In addition, molecular docking investigations showed that harmaline (-8.90 kcal/mol), harmalol (-8.56 kcal/mol), and ibogaine (-8.75 kcal/mol) exhibited binding affinities comparable to the control molecule, LSD (-9.14 kcal/mol), indicating potential agonistic activity at serotonin 5-HT2A receptor.

These findings provide insights into the potential therapeutic benefits of S. undulata, supporting its traditional use as a psychoactive plant. This study investigated the chemical constituents and potential serotonergic agonist activity of S. undulata for the first time. While promising, further research is necessary to uncover additional medicinal properties associated with the identified phytochemical components.

Leishmaniasis is responsible for approximately 65,000 annual deaths. Various Leishmania species are the predominant cause of visceral, cutaneous, or mucocutaneous leishmaniasis, affecting millions worldwide. The lack of a vaccine, emergence of resistance, and undesirable side effects caused by antileishmanial medications have prompted researchers to look for novel therapeutic approaches to treat this disease. Antimicrobial peptides (AMPs) offer an alternative for promoting the discovery of new drugs.

In this study, we detail the synthesis process and investigate the antileishmanial activity against Leishmania (Viannia) braziliensis for peptides belonging to the dermaseptin (DS) family and their synthetic analogs. The MTT assay was performed to investigate the cytotoxicity of these peptides on the murine macrophage cell line RAW 264.7. Subsequently, we performed molecular modeling analysis to explore the structure-function correlation of the derivatives interacting with the parasitic membrane.

All examined derivatives displayed concentration-dependent antileishmanial effect at low concentrations. Their effectiveness varied according to the peptide's proprieties. Notably, peptides with higher levels of charge demonstrated the most pronounced activities. Cytotoxicity assays showed that all the tested peptides were not cytotoxic compared to the tested conventional drug. The structure-function relationships demonstrated that the charged N-terminus could be responsible for the antileishmanial effect observed on promastigotes.

Collectively, these results propose that dermaseptins (DS) might offer potential as promising candidates for the development of effective antileishmanial therapies.

Honey possesses several positive properties, making it effective in wound healing mechanisms. However, very little information is available on the different honey types for wound healing activity.

In the first “Academy of Sciences”, a public engagement project with high school students, we assessed the properties of thirteen kinds of honey from the Piedmont area (Nord West Italy). In particular, we characterized the color intensity (by Pfund scale), total phenolic content (TPC), total flavonoid content (TFC), H2O2 production, and wound closure rate.

Then, we tried to verify the presence of a correlation between these parameters, finding a positive correlation between H2O2 and wound closure rate.

These data pave the way to characterize different types of Italian honey to completely understand its potential.