Current Topics in Medicinal Chemistry - Online First

Zika virus (ZIKV), a flavivirus primarily transmitted by Aedes aegypti, became a major global health concern during the 2015–2016 outbreak, particularly in Brazil. Its association with congenital malformations and neurological disorders underscores the urgent need for effective therapeutic interventions. This review explores molecular targets for ZIKV treatment within the Brazilian context.

A systematic search was conducted using PubMed, ScienceDirect, and Scopus for studies published between 2004 and 2024. Inclusion criteria focused on studies identifying druggable molecular targets related to viral replication, immune evasion, or host-virus interactions. Key search terms included “Zika virus,” “molecular targets,” “Brazil,” “antiviral,” and “drug discovery.”

The review identified several critical viral proteins, NS1, NS3, NS5, and the envelope protein, as potential drug targets. Host cellular factors essential for viral survival were also highlighted. Technologies such as high-throughput screening, molecular docking, and structural genomics contributed significantly to the identification and validation of these targets.

Although promising targets have been identified, therapeutic development is hindered by the genetic variability of ZIKV and its antigenic similarity to other flaviviruses, notably the dengue virus. These challenges complicate the specificity and efficacy of drugs. Nevertheless, Brazil has made strides in research infrastructure and collaborations to tackle these obstacles.

This review synthesizes current knowledge on ZIKV molecular targets and ongoing drug discovery efforts. The findings support the strategic development of antivirals and emphasize the necessity for sustained investment in research to mitigate future ZIKV outbreaks in Brazil and globally.

Obesity, a widespread health condition marked by excessive body fat, markedly elevates the risk of chronic diseases and has emerged as a major global health issue. Chrysin, a flavonoid with promising health benefits, exhibits potent antioxidant and anti-inflammatory properties. This study seeks to examine the impact of chitosan chrysin nanoparticles (Chrysin-CSNPS) on obesity induced by a high-fat diet (HFD) in male rats.

Rats were fed a high-fat diet for 4 weeks to induce obesity, followed by a 4-week treatment period. Thirty rats were allocated into five groups (six rats per group): control (dist. water, orally), HFD control (dist. water, orally), HFD + chrysin (500 mg/kg, orally), HFD + chitosan-NP (60 mg/kg, orally), and HFD + Chrysin-CSNPS (60 mg/kg, orally).

In silico studies revealed that chrysin has a binding energy value of −8.8 kcal/mol to fat mass and obesity-associated (FTO) protein. Also, Chrysin is identified as an inhibitor of several cytochrome P450 enzymes, specifically CYP1A2, CYP2D6, and CYP3A4. Albumin, high-density lipoprotein cholesterol, glutathione, and nitric oxide levels rose, whereas glucose, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, creatinine, urea, total cholesterol, triglycerides, malondialdehyde, and nitric oxide levels fell upon Chrysin-CSNPS treatment. The histological examination revealed a significant enhancement in the structures of the liver and kidneys.

These findings suggest that chrysin could potentially inhibit FTO activity, thereby contributing to a reduction in obesity-related phenotypes. The compound that satisfied Lipinski’s criteria was selected for toxicity prediction.

Chrysin-CSNPS have hypolipidemic properties and an antioxidant role, reducing HFD consequences in the liver and kidney.

This study aims to elucidate the mechanisms underlying Dementia using bioinformatics analysis and machine learning algorithms, to identify novel therapeutic targets for its clinical management.

Gene expression datasets related to dementia were sourced from the GEO database. Differentially expressed genes (DEGs) were identified using R, and key module genes were determined through the Weighted Gene Co-expression Network Analysis (WGCNA) method. Oligodendrocyte (OL) related targets were retrieved from the GeneCards database. The intersecting genes from DEGs, WGCNA, and OL were analyzed using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. Subsequently, three machine learning algorithms were employed to pinpoint core genes associated with OL in dementia. The CIBERSORT algorithm was used to evaluate the abundance of 22 immune cell types and their correlation with Dementia-related immune infiltration. Validation was carried out via quantitative reverse transcription polymerase chain reaction (RT-qPCR).

Through bioinformatics and machine learning techniques, six core OL genes associated with Dementia were identified, notably C1QA, CD163, and TGFB2, which showed elevated expression in Dementia. Immune cell infiltration analysis indicated that several immune cell types may contribute to Dementia's pathogenesis, and RT-qPCR results corroborated the bioinformatics findings.

The discovered genes may contribute to dementia pathogenesis through oligodendrocyte dysfunction and neuroimmune interactions. Notably, TGFB2 and complement-related genes (C1QA, CD163) suggest involvement in both myelination defects and neuroinflammation, highlighting their therapeutic potential.

The six feature genes: TGFB2, C1QA, CD163, ACTG1, WIF1, and OPALIN are significantly linked to Dementia.

Colorectal cancer (CRC) remains a significant global health challenge due to its high incidence and mortality rates. The disease's complexity and heterogeneity impede early diagnosis and effective treatment. The study aims to investigate the role of Tetraspanin 11 (TSPAN11) in CRC, exploring its potential as a prognostic biomarker and immunotherapy target through bioinformatics analysis and experimental validation.

Pan-cancer patient data were obtained from The Cancer Genome Atlas (TCGA) and the GSE71187 dataset, including 672 CRC tissues and 51 adjacent normal tissues. Differential expression analysis, Kaplan-Meier survival analysis, gene set enrichment analysis (GSEA), and immune infiltration assessment were performed. TSPAN11 expression was validated in CRC cell lines using quantitative reverse transcription PCR (qRT-PCR).

TSPAN11 was significantly downregulated in CRC tissues compared to normal tissues (p < 0.001), with lower expression associated with poorer overall survival (OS; p = 0.011) and disease-specific survival (DSS; p = 0.038). Multivariate analysis identified TSPAN11 as an independent prognostic factor (p = 0.045). TSPAN11 expression was linked to key pathways such as ECM receptor interaction and TGF-β signaling, and correlated with immune infiltration, immune checkpoint genes, tumor mutational burden (TMB), microsatellite instability (MSI), and drug sensitivity.

The findings suggest that TSPAN11 may influence CRC progression through multiple biological pathways and immune-related mechanisms. Its downregulation is associated with poorer prognosis and immune evasion, highlighting its potential as a biomarker and therapeutic target. However, validation in larger cohorts and elucidation of underlying mechanisms are needed to confirm these results and translate them into clinical practice.

TSPAN11 may serve as a promising prognostic biomarker and immunotherapy target in CRC. Its associations with clinical outcomes, immune features, and drug sensitivity underscore its potential for improving CRC diagnosis and treatment strategies.

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder affecting 70-75% of women. This condition is frequently linked with large and dysfunctional ovaries, high levels of androgens, and insulin resistance. A variety of conventional treatments, including metformin, oral contraceptives, and anti-androgen agents, have been used to treat PCOS and its complications, but they have been linked to several negative side effects, including hyperkalemia, weight gain, cardiovascular and hepatic toxicity, vitamin B12 and folic acid deficiency. As a result, there is growing interest in natural methods as complementary or alternative approaches to mitigate these side effects. According to several studies, traditionally used Natural oils (NOs) from various sources have been utilized to identify their ameliorating characteristics against PCOS. The paper aims to study pre-clinical investigations and clinical studies of NOs from different sources against PCOS and gives a comprehensive overview of controlling PCOS. Also, it highlights and tabulates the prominent bioactive phytoconstituents from the reported NOs and their mechanism of action.

For this review purpose, the authors have gone through a vast number of scientific literature from different scientific databases like Google Scholar, ScienceDirect, Web of Science, and PubMed.

Mentha spicata L., Foeniculum vulgare Mill., Linum usitatissimum L., Nigella sativa L., Bambusa bambos (L.) Voss, Thuja occidentalis L., Syzygium aromaticum L., Pimpinella anisum L., Rosa canina L., Cocos nucifera L., Oenothera biennis L., Corylus avellana L., and fish oil have been reported to have anti-PCOS activity by maintaining body weight, testosterone, LH, FSH levels, and improving ovarian cysts.

NOs derived from plant and animal sources show promise in treating PCOS by balancing hormone levels, enhancing ovarian morphology, and alleviating metabolic symptoms. However, significant clinical trials and molecular research are required to evaluate their therapeutic potential, identify suitable dosages, investigate their precise mechanisms of action, and ensure long-term safety and efficacy in PCOS management.

Further research is needed to understand the molecular mechanisms of NOs responsible for anti-PCOS activity. Studies are needed to concentrate on their mechanisms of action, routes of impact, safe dosage, and potential side effects to ensure their efficacy and safety in treating PCOS.

Current trends in peptide synthesis protocols have emerged as the most attractive domain in the field of pharma and medicine. Since most of the peptide/peptidomimetic-based molecules serve as potential candidates for many diseases, as they are bioavailable molecules.

We present the synthesis of bioactive peptides through TAGGING approach with the help of TAG-OH as a linker to the N^α-protected amino acid.

FRDEHKK and NKDRG are two peptides that possess antioxidant and antiproliferative activity, and their in-silico investigations reveal that they exhibit anticancer properties when bound to the AXL kinase and EGFR proteins.

This TAG method enables the easy isolation of peptides at each step as solids, and all the impurities were washed off by simple filtration. The method allows a bulk-scale preparation of the peptides without any difficulty, and hence the protocol is highly efficient for the production of peptides of therapeutic importance.

The two peptides FRDEHKK and NKDRG were isolated as fine solids with 82% and 85% yield and were characterized by NMR and MASS spectroscopy. In-silico studies reveal FRDEHKK and NKDRG peptides exhibit good affinity towards EGFR and AXL kinase.

Skin cutaneous melanoma (SKCM) is a life-threatening malignancy, and pyroptosis-mediated inflammatory response is associated with SKCM progression. We aimed to uncover the underlying pathogenesis of SKCM based on pyroptosis features.

The single-cell and bulk RNA-seq data and clinical information of SKCM patients were downloaded from the TCGA and GEO databases, and the REACTOME_PYROPTOSIS.v2024.1.Hs.gmt from the MSigDB database was used for Gene Set Enrichment Analysis (GSEA). Differentially expressed gene (DEG) analysis was performed utilizing the “limma” R package, and the “GSVA” R package was used for the analysis of pyroptosis pathway activation. In addition, scRNA-seq analysis and cell communication analysis were carried out by employing the “Seurat” R package and “CellChat” R package, respectively. Gene expression was measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR), while cell counting kit-8 (CCK-8), wound healing, and Transwell assays were carried out to assess cell proliferation, migration, and invasion, respectively.

DEGs analysis detected no significant pyroptosis-related DEGs. Analysis of the expression of two representative pyroptosis genes (GZMA and GSDMB) revealed that GZMA was significantly upregulated in the SKCM tissues, but the expression of GSDMB was downregulated. The pyroptosis pathway was not activated in the tumor group. In addition, we observed that high expression of GZMA and GSDMB was closely associated with a favorable outcome in SKCM. The two genes were downregulated in SKCM cells, while the overexpression of GZMA significantly impaired the proliferation, migration, and invasion ability of SKCM cells. Nine main cell subpopulations were identified, and GZMA was specifically overexpressed in CD8+ T cells. Gene function analysis revealed that specific genes of CD8+ T cells were enriched in cell death-related and inflammation activation pathways. Cell communication demonstrated that CD8+ T cells interacted with melanocytes through the CD99-CD99 and HLA-C-KIR2DL3 ligand-receptor pairs.

Based on the pyroptosis features in SKCM, this study found that blocking GZMA protein in CD8+ T cells within melanocytes may be the potential underlying pathogenesis for tumor immune escape in cancer.