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Design, Synthesis, and Unprecedented Interactions of Covalent Dipeptide-Based Inhibitors of SARS-CoV-2 Main Protease and Its Variants Displaying Potent Antiviral Activity.
J Med Chem
January 2025
Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
The main protease (M) of SARS-CoV-2 is a key drug target for the development of antiviral therapeutics. Here, we designed and synthesized a series of small-molecule peptidomimetics with various cysteine-reactive electrophiles. Several compounds were identified as potent SARS-CoV-2 M inhibitors, including compounds (IC = 0.
View Article and Find Full Text PDFNR1D1 Inhibition Enhances Autophagy and Mitophagy in Alzheimer's Disease Models.
Aging Dis
January 2025
Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog 1478, Norway.
Alzheimer's disease (AD) is marked by extracellular beta-amyloid (Aβ) plaques and intracellular Tau tangles, leading to progressive cognitive decline and neuronal dysfunction. Impaired autophagy, a process by which a cell breaks down and destroys damaged or abnormal proteins and other substances, contributes to AD progression. This study investigated Nuclear Receptor Subfamily 1 Group D Member 1 (NR1D1) as a potential therapeutic target for modulating autophagy.
View Article and Find Full Text PDFNitrile-aminothiol bioorthogonal near-infrared fluorogenic probes for ultrasensitive in vivo imaging.
Nat Commun
January 2025
State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Bioorthogonal chemistry-mediated self-assembly holds great promise for dynamic molecular imaging in living organisms. However, existing approaches are limited to nanoaggregates with 'always-on' signals, suffering from high signal-to-background ratio (SBR) and compromised detection sensitivity. Herein we report a nitrile-aminothiol (NAT) bioorthogonal fluorogenic probe (CyNA-SS-FK) for ultrasensitive diagnosis of orthotopic hepatocellular carcinoma.
View Article and Find Full Text PDFSuppression of Bone Formation and Resorption by the Deletion of Complex Gangliosides.
In Vivo
December 2024
Department of Pharmacology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan;
Background/aim: Gangliosides regulate bone formation and resorption. Bone formation is reduced in mice lacking ganglioside GM2/GD2 synthase due to a decrease in osteoblasts. However, the effects of the loss of complex gangliosides by the deletion of both GM2/GD2 and GD3 synthases are unknown.
View Article and Find Full Text PDFInhibition of intracellular versus extracellular cathepsin D differentially alters the liver lipidome of mice with metabolic dysfunction-associated steatohepatitis.
FEBS J
December 2024
Department of Genetics and Cell Biology, Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, The Netherlands.
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) progressing to metabolic dysfunction-associated steatohepatitis (MASH), characterized by hepatic inflammation, has significantly increased in recent years due to unhealthy dietary practices and sedentary lifestyles. Cathepsin D (CTSD), a lysosomal protease involved in lipid homeostasis, is linked to abnormal lipid metabolism and inflammation in MASH. Although primarily intracellular, CTSD can be secreted extracellularly.
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