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37 pages, 8170 KiB

Open AccessArticle

Drug Repurposing to Inhibit Oncostatin M in Crohn’s Disease

by Faranak Bahramimehr, Axel Guthart, Stefanie Kurz, Yuanping Hai, Mona Dawood, Rümeysa Yücer, Nasim Shahhamzehei, Ralf Weiskirchen, Wilfried Roth, Wolfgang Stremmel, Gerhard Bringmann and Thomas Efferth

Molecules 2025, 30(9), 1897; https://doi.org/10.3390/molecules30091897 - 24 Apr 2025

Viewed by 125

Abstract

Crohn’s disease is an inflammatory bowel disease (IBD) that currently lacks satisfactory treatment options. Therefore, new targets for new drugs are urgently needed to combat this disease. In the present study, we investigated the transcriptomics-based mRNA expression of intestinal biopsies from patients with [...] Read more.

Crohn’s disease is an inflammatory bowel disease (IBD) that currently lacks satisfactory treatment options. Therefore, new targets for new drugs are urgently needed to combat this disease. In the present study, we investigated the transcriptomics-based mRNA expression of intestinal biopsies from patients with Crohn’s disease. We compared the mRNA expression profiles of the ileum and colon of patients with those of healthy individuals. A total of 72 genes in the ileum and 33 genes in the colon were differentially regulated. Among these, six genes were overexpressed in both tissues, including IL1B, TCL1A, HCAR3, IGHG1, S100AB, and OSM. We further focused on OSM/oncostatin M. To confirm the responsiveness of intestinal tissues from patients with Crohn’s disease to oncostatin M inhibition, we examined the expression of the oncostatin M receptor using immunohistochemistry in patient biopsies as well as in kindlin-1^−/− and kindlin-2^−/− knockout mice, which exhibit an inflammatory bowel disease (IBD) phenotype, and found strong oncostatin M expression in all samples examined. Next, we conducted a drug-repurposing study using the supercomputer MOGON and bioinformatic methods. A total of 13 candidate compounds out of 1577 FDA-approved drugs were identified by PyRx-based virtual drug screening and AutoDock-based molecular docking. Their lowest binding energies (LBEs) ranged from −10.46 (±0.08) to −8.77 (±0.08) kcal/mol, and their predicted inhibition constants (pK_i) ranged from 21.62 (±2.97) to 373.78 (±36.78) nM. Ecamsule has an interesting stereostructure with two C₂-symmetric enantiomers (1S,4R-1′S,4′R and 1R,4S-1′R,4′S) (1a and 1b) and one meso diastereomer (1S,4R-1′R,4′S) (1c). These three stereoisomers showed strong, albeit differing, binding affinities in molecular docking. As examined by nuclear magnetic resonance and polarimetry, the 1S,4R-1′S,4′R isomer was the stereoisomer present in our commercially available preparations used for microscale thermophoresis. Ecamsule (1a) was chosen for in vitro validation using recombinant oncostatin M and microscale thermophoresis. Considerable dissociation constants were obtained for ecamsule after three repetitions with a K_d value of 11.36 ± 2.83 µM. Subsequently, we evaluated, by qRT-PCR, the efficacy of ecamsule (1a) as a potential drug that could prevent oncostatin M activation by inhibiting downstream inflammatory marker genes (IL6, TNFA, and CXCL11). In conclusion, we have identified oncostatin M as a promising new drug target for Crohn’s disease through transcriptomics and ecamsule as a potential new drug candidate for Crohn’s disease through a drug-repurposing approach both in silico and in vitro. Full article

(This article belongs to the Special Issue Bioorganic Chemistry in Europe)

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16 pages, 2044 KiB

Open AccessArticle

A Targeted Mass Spectrometric Approach to Evaluate the Anti-Inflammatory Activity of the Major Metabolites of Foeniculum vulgare Mill. Waste in Human Bronchial Epithelium

by Maria Assunta Crescenzi, Hector Gallart-Ayala, Cristiana Stellato, Ada Popolo, Julijana Ivanisevic, Sonia Piacente and Paola Montoro

Molecules 2025, 30(7), 1407; https://doi.org/10.3390/molecules30071407 - 21 Mar 2025

Viewed by 235

Abstract

Fennel waste is rich in compounds that may have beneficial effects on human health. For this reason, the most abundant metabolites in fennel were isolated as the following: quercetin-3-O-glucoside, quinic acid, 1,5-dicaffeoylquinic acid, kaempferol-3-O-glucuronide, and quercetin-3-O-glucuronide. After [...] Read more.

Fennel waste is rich in compounds that may have beneficial effects on human health. For this reason, the most abundant metabolites in fennel were isolated as the following: quercetin-3-O-glucoside, quinic acid, 1,5-dicaffeoylquinic acid, kaempferol-3-O-glucuronide, and quercetin-3-O-glucuronide. After inducing inflammation in human bronchial epithelial cells by stimulating them with IL-1β, the cells were treated with the specialized Foeniculum vulgare metabolites at different concentrations to assess their anti-inflammatory effect. Eicosanoids, fatty acids, and sphingolipids were extracted from the cell medium and quantified by UPLC-ESI-QTRAP-MS/MS analysis. The anti-inflammatory activity of the metabolites isolated from fennel waste was demonstrated. They were able to alleviate the inflammatory state in human bronchial epithelium by modulating the metabolic expression of both pro- and anti-inflammatory eicosanoids, fatty acids, and sphingolipids. These findings suggest the potential use of fennel waste in the production of dietary supplements to alleviate the symptoms of chronic inflammatory diseases like asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF), where the continuous use of antiphlogistics may have significant side effects. Full article

(This article belongs to the Special Issue Bioorganic Chemistry in Europe)

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22 pages, 2793 KiB

Open AccessArticle

Effect of Glycoconjugation on Cytotoxicity and Selectivity of 8-Aminoquinoline Derivatives Compared to 8-Hydroxyquinoline

by Gabriela Pastuch-Gawołek and Julia Szreder

Molecules 2025, 30(2), 427; https://doi.org/10.3390/molecules30020427 - 20 Jan 2025

Viewed by 816

Abstract

Numerous emerging chemotherapeutic agents incorporate N-heterocyclic fragments in their structures, with the quinoline skeleton being particularly significant. Our recent works have focused on glycoconjugates of 8-hydroxyquinoline (8-HQ), which demonstrated enhanced bioavailability and solubility compared to their parent compounds, although they fell short [...] Read more.

Numerous emerging chemotherapeutic agents incorporate N-heterocyclic fragments in their structures, with the quinoline skeleton being particularly significant. Our recent works have focused on glycoconjugates of 8-hydroxyquinoline (8-HQ), which demonstrated enhanced bioavailability and solubility compared to their parent compounds, although they fell short in selectivity. In this study, our objective was to improve the selectivity of glycoconjugates by replacing the oxygen atom with nitrogen by substituting the 8-HQ moiety with 8-aminoquinoline (8-AQ). The 8-AQ derivatives were functionalized through the amino group and linked to sugar derivatives (D-glucose or D-galactose) that were modified with an azide, alkylazide, or propargyl group at the anomeric position by copper(I)-catalyzed 1,3-dipolar azido-alkyne cycloaddition (CuAAC). The resulting glycoconjugates, as well as their potential metabolites, were evaluated for their ability to inhibit the proliferation of cancer cell lines (including HCT 116 and MCF-7) and a healthy cell line (NHDF-Neo). Two of the synthesized glycoconjugates (17 and 18) demonstrated higher cytotoxicity than their oxygen-containing counterparts and showed improved selectivity for cancer cells, thus enhancing their anticancer potential. Furthermore, it was found that glycoconjugates exhibited greater cytotoxicity in comparison to their potential metabolites. Full article

(This article belongs to the Special Issue Bioorganic Chemistry in Europe)

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19 pages, 740 KiB

Open AccessArticle

Synthesis and Antiviral Evaluation of 5-(4-Aryl-1,3-butadiyn-1-yl)-uridines and Their Phosphoramidate Pronucleotides

by Evan Saillard, Otmane Bourzikat, Koffi Assa, Vincent Roy and Luigi A. Agrofoglio

Molecules 2025, 30(1), 96; https://doi.org/10.3390/molecules30010096 - 29 Dec 2024

Viewed by 1200

Abstract

The emergence of RNA viruses driven by global population growth and international trade highlights the urgent need for effective antiviral agents that can inhibit viral replication. Nucleoside analogs, which mimic natural nucleotides, have shown promise in targeting RNA-dependent RNA polymerases (RdRps). Starting from [...] Read more.

The emergence of RNA viruses driven by global population growth and international trade highlights the urgent need for effective antiviral agents that can inhibit viral replication. Nucleoside analogs, which mimic natural nucleotides, have shown promise in targeting RNA-dependent RNA polymerases (RdRps). Starting from protected 5-iodouridine, we report the synthesis of hitherto unknown C5-substituted-(1,3-diyne)-uridines nucleosides and their phosphoramidate prodrugs. The modifications at C5 include 4-(trifluoromethyl)benzene (a), 4-pentyl-benzene (b), 3,5-dimethoxy-benzene (c), 4-(trifluoromethoxy)benzene (d), 3-aniline (e), 4-pyridine (f), 3-thiophene (g), C₆H₁₃ (h), 2-pyrimidine (i), cyclopropyl (j), and phenyl (k) groups. These compounds were synthesized using Sonogashira palladium-catalyzed reactions and nickel–copper-catalyzed C-H activation between various alkynes, yielding between 25% and 67%. The antiviral activities of obtained compounds were measured through HTS against RNA viruses including influenza H1N1 and H3N2, human respiratory syncytial virus (RSV), SARS-CoV-2, Zika, hepatitis C virus (HCV), Hepatitis E virus (HEV), as well as against coronavirus (HCoV-229E). Unfortunately, none of them showed promising antiviral activity, with less than 85% inhibition observed in the cell viability screening of infected cells. Full article

(This article belongs to the Special Issue Bioorganic Chemistry in Europe)

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12 pages, 1266 KiB

Open AccessArticle

The Role of Unsaturated Fatty Acid-Rich Dairy Products in Adipocyte Metabolism

by Manuela Machado, Eduardo M. Costa, Sara Silva, Ana Maria Gomes and Manuela Pintado

Molecules 2024, 29(23), 5502; https://doi.org/10.3390/molecules29235502 - 21 Nov 2024

Viewed by 929

Abstract

This study investigated the fatty acid profile, permeability, and metabolic effects of a functional yogurt enriched with pomegranate oil, focusing on its impact on lipid metabolism and inflammatory responses. The yogurt’s fatty acid composition was primarily composed of long-chain polyunsaturated fatty acids (54.37%), [...] Read more.

This study investigated the fatty acid profile, permeability, and metabolic effects of a functional yogurt enriched with pomegranate oil, focusing on its impact on lipid metabolism and inflammatory responses. The yogurt’s fatty acid composition was primarily composed of long-chain polyunsaturated fatty acids (54.37%), followed by saturated (29.34%) and monounsaturated fatty acids (16.36%). During in vitro digestion, a shift in fatty acid profile was observed, with a decrease in polyunsaturated and saturated fatty acids and a slight increase in monounsaturated fatty acids due to hydrolysis. This study further analyzed fatty acid permeability across Caco-2/HT29-MTX monolayers and 3T3-L1 cell uptake, revealing higher permeability for saturated fatty acids than unsaturated ones. In 3T3-L1 cells, permeated fatty acids induced higher lipolysis and increased adiponectin secretion without affecting leptin levels. Cytokine analysis indicated a decrease in pro-inflammatory markers, such as MCP-1, and a significant increase in anti-inflammatory cytokines like IL-10, suggesting potential benefits in reducing obesity-related inflammation. These results underscore the role of functional yogurts enriched with polyunsaturated fatty acids as promising agents for modulating lipid metabolism and inflammatory responses. Full article

(This article belongs to the Special Issue Bioorganic Chemistry in Europe)

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Review

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25 pages, 3102 KiB

Open AccessReview

The HELP-UnaG Fusion Protein as a Bilirubin Biosensor: From Theory to Mature Technological Development

by Paola Sist, Ranieri Urbani, Federica Tramer, Antonella Bandiera and Sabina Passamonti

Molecules 2025, 30(3), 439; https://doi.org/10.3390/molecules30030439 - 21 Jan 2025

Viewed by 1138

Abstract

HUG is the HELP-UnaG recombinant fusion protein featuring the typical functions of both HELP and UnaG. In HUG, the HELP domain is a thermoresponsive human elastin-like polypeptide. It forms a shield enwrapping the UnaG domain that emits bilirubin-dependent fluorescence. Here, we recapitulate the [...] Read more.

HUG is the HELP-UnaG recombinant fusion protein featuring the typical functions of both HELP and UnaG. In HUG, the HELP domain is a thermoresponsive human elastin-like polypeptide. It forms a shield enwrapping the UnaG domain that emits bilirubin-dependent fluorescence. Here, we recapitulate the technological development of this bifunctional synthetic protein from the theoretical background of its distinct protein moieties to the detailed characterization of its macromolecular and functional properties. These pieces of knowledge are the foundations for HUG production and application in the fluorometric analysis of bilirubin and its congeners, biliverdin and bilirubin glucuronide. These bile pigments are metabolites that arise from the catabolism of heme, the prosthetic group of cytochromes, hemoglobin and several other intracellular enzymes engaged in electron transfer, oxygen transport and protection against oxygen free radicals. The HUG assay is a powerful, user-friendly and affordable analytical tool that alone supports research at each level of complexity or taxonomy of living entities, from enzymology, cell biology and pathophysiology to veterinary and clinical sciences. Full article

(This article belongs to the Special Issue Bioorganic Chemistry in Europe)

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32 pages, 3523 KiB

Open AccessReview

Agents Targeting the Bacterial Cell Wall as Tools to Combat Gram-Positive Pathogens

by Aliaksandr Zhydzetski, Zuzanna Głowacka-Grzyb, Michal Bukowski, Tomasz Żądło, Emilia Bonar and Benedykt Władyka

Molecules 2024, 29(17), 4065; https://doi.org/10.3390/molecules29174065 - 27 Aug 2024

Cited by 5 | Viewed by 3884

Abstract

The cell wall is an indispensable element of bacterial cells and a long-known target of many antibiotics. Penicillin, the first discovered beta-lactam antibiotic inhibiting the synthesis of cell walls, was successfully used to cure many bacterial infections. Unfortunately, pathogens eventually developed resistance to [...] Read more.

The cell wall is an indispensable element of bacterial cells and a long-known target of many antibiotics. Penicillin, the first discovered beta-lactam antibiotic inhibiting the synthesis of cell walls, was successfully used to cure many bacterial infections. Unfortunately, pathogens eventually developed resistance to it. This started an arms race, and while novel beta-lactams, either natural or (semi)synthetic, were discovered, soon upon their application, bacteria were developing resistance. Currently, we are facing the threat of losing the race since more and more multidrug-resistant (MDR) pathogens are emerging. Therefore, there is an urgent need for developing novel approaches to combat MDR bacteria. The cell wall is a reasonable candidate for a target as it differentiates not only bacterial and human cells but also has a specific composition unique to various groups of bacteria. This ensures the safety and specificity of novel antibacterial agents that target this structure. Due to the shortage of low-molecular-weight candidates for novel antibiotics, attention was focused on peptides and proteins that possess antibacterial activity. Here, we describe proteinaceous agents of various origins that target bacterial cell wall, including bacteriocins and phage and bacterial lysins, as alternatives to classic antibiotic candidates for antimicrobial drugs. Moreover, advancements in protein chemistry and engineering currently allow for the production of stable, specific, and effective drugs. Finally, we introduce the concept of selective targeting of dangerous pathogens, exemplified by staphylococci, by agents specifically disrupting their cell walls. Full article

(This article belongs to the Special Issue Bioorganic Chemistry in Europe)

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22 pages, 1115 KiB

Open AccessFeature PaperReview

A Phenotypic Approach to the Discovery of Potent G-Quadruplex Targeted Drugs

by Stephen Neidle

Molecules 2024, 29(15), 3653; https://doi.org/10.3390/molecules29153653 - 1 Aug 2024

Cited by 11 | Viewed by 3266

Abstract

G-quadruplex (G4) sequences, which can fold into higher-order G4 structures, are abundant in the human genome and are over-represented in the promoter regions of many genes involved in human cancer initiation, progression, and metastasis. They are plausible targets for G4-binding small molecules, which [...] Read more.

G-quadruplex (G4) sequences, which can fold into higher-order G4 structures, are abundant in the human genome and are over-represented in the promoter regions of many genes involved in human cancer initiation, progression, and metastasis. They are plausible targets for G4-binding small molecules, which would, in the case of promoter G4s, result in the transcriptional downregulation of these genes. However, structural information is currently available on only a very small number of G4s and their ligand complexes. This limitation, coupled with the currently restricted information on the G4-containing genes involved in most complex human cancers, has led to the development of a phenotypic-led approach to G4 ligand drug discovery. This approach was illustrated by the discovery of several generations of tri- and tetra-substituted naphthalene diimide (ND) ligands that were found to show potent growth inhibition in pancreatic cancer cell lines and are active in in vivo models for this hard-to-treat disease. The cycles of discovery have culminated in a highly potent tetra-substituted ND derivative, QN-302, which is currently being evaluated in a Phase 1 clinical trial. The major genes whose expression has been down-regulated by QN-302 are presented here: all contain G4 propensity and have been found to be up-regulated in human pancreatic cancer. Some of these genes are also upregulated in other human cancers, supporting the hypothesis that QN-302 is a pan-G4 drug of potential utility beyond pancreatic cancer. Full article

(This article belongs to the Special Issue Bioorganic Chemistry in Europe)

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