| 1. |
- Haid, Sibylle, et al.
(author)
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Repurposing screen identifies novel candidates for broad-spectrum coronavirus antivirals and druggable host targets
- 2024
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In: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 68:3
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Journal article (peer-reviewed)abstract
- Libraries composed of licensed drugs represent a vast repertoire of molecules modulating physiological processes in humans, providing unique opportunities for the discovery of host-targeting antivirals. We screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) repurposing library with approximately 12,000 molecules for broad-spectrum coronavirus antivirals and discovered 134 compounds inhibiting an alphacoronavirus and mapping to 58 molecular target categories. Dominant targets included the 5-hydroxytryptamine receptor, the dopamine receptor, and cyclin-dependent kinases. Gene knock-out of the drugs’ host targets including cathepsin B and L (CTSB/L; VBY-825), the aryl hydrocarbon receptor (AHR; Phortress), the farnesyl-diphosphate farnesyltransferase 1 (FDFT1; P-3622), and the kelch-like ECH-associated protein 1 (KEAP1; Omaveloxolone), significantly modulated HCoV-229E infection, providing evidence that these compounds inhibited the virus through acting on their respective host targets. Counter-screening of all 134 primary compound candidates with SARS-CoV-2 and validation in primary cells identified Phortress, an AHR activating ligand, P-3622-targeting FDFT1, and Omaveloxolone, which activates the NFE2-like bZIP transcription factor 2 (NFE2L2) by liberating it from its endogenous inhibitor KEAP1, as antiviral candidates for both an Alpha- and a Betacoronavirus. This study provides an overview of HCoV-229E repurposing candidates and reveals novel potentially druggable viral host dependency factors hijacked by diverse coronaviruses.
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| 2. |
- Jimidar, Claire Cheyenne, et al.
(author)
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Masked Amino Trimethyl Lock (H2N-TML) Systems: New Molecular Entities for the Development of Turn-On Fluorophores and Their Application in Hydrogen Sulfide (H2S) Imaging in Human Cells
- 2022
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In: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 28
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Journal article (peer-reviewed)abstract
- Masked trimethyl lock (TML) systems as molecular moieties enabling the bioresponsive release of compounds or dyes in a controlled temporal and spatial manner have been widely applied for the development of drug conjugates, prodrugs or molecular imaging tools. Herein, we report the development of a novel amino trimethyl lock (H2N-TML) system as an auto-immolative molecular entity for the release of fluorophores. We designed Cou-TML-N3 and MURh-TML-N3, two azide-masked turn-on fluorophores. The latter was demonstrated to selectively release fluorescent MURh in the presence of physiological concentrations of the redox-signaling molecule H2S in vitro and was successfully applied to image H2S in human cells.
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| 3. |
- Miethke, Marcus, et al.
(author)
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Towards the sustainable discovery and development of new antibiotics
- 2021
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In: Nature Reviews Chemistry. - : Springer Nature. - 2397-3358. ; 5:10, s. 726-749
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Research review (peer-reviewed)abstract
- An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.
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| 4. |
- Villanova, Valeria, et al.
(author)
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Biological and chemical characterization of new isolated halophilic microorganisms from saltern ponds of Trapani, Sicily
- 2021
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In: Algal Research. - : Elsevier BV. - 2211-9264. ; 54
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Journal article (peer-reviewed)abstract
- Halophilic microorganisms inhabiting hypersaline environments such as salt lakes, Dead Sea, or salt evaporation ponds, have acquired specific cell adaptation to grow within stressful conditions. In this study, we isolated heterotrophic and autotrophic microorganisms from several saltern ponds located at the Natural Reserve “Saline di Trapani e Paceco”, Sicily, Italy. The aim of the study was to investigate the biotechnological potential of new microbial strains from saltern ponds, by capturing their biological and chemical diversity. After the isolation and identification of the sampled strains, their growth capacity was determined under low and high salinity conditions. The metabolomic profiles of heterotrophs and pigments production of photosynthetic organisms were analyzed. In parallel, antiproliferative tests on human cell lines were conducted with total extracts coming from the microorganism cultures, together with repair activity assessment of non-cytotoxic extracts. Some of the isolated strains were found to synthetize known bioactive molecules and to exert bioactivity on human cells. In particular, the high salinity increases cell repair activity, probably due to an higher production of antioxidants pigments (e.g. lutein and fucoxanthin) from photosynthetic microorganisms; same culture condition augment also concentration of molecules with interesting bioactivities, such as ectoine, betaine, trigonelline, amino acids and oxiglutathione from heterotrophic microorganisms. In conclusion, this work represents the first study on the isolation of halophilic microorganisms populating the ‘Trapani-Paceco’ saltern and shows how an interdisciplinary investigation based on marine microbiology, cell biology, and modern metabolomics can disclose their biotechnological potential.
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