Duvoglustat Hydrochloride

Mytilus live in water as sessile filter feeders, and the mantle tissue plays an important role in their immune defense. However, the overall knowledge of the immunity of this tissue remains limited. Peptidoglycan (PGN) and lipopolysaccharide (LPS) are the most representative microbe-associated molecular patterns (MAMPs) that play roles in the immune stimulation of host cells. In the present study, ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS)-based metabolomic analysis was performed to understand the precise regulatory mechanism at the molecular level in the Mytilus mantle in response to PGN and LPS stress. Moreover, the antioxidant ability and free amino acid composition of the mantle, and the antimicrobial activities of mantle mucus were evaluated. Our results revealed that LPS and PGN stresses had different effects on the mantle's free amino acid composition and antioxidant ability, and the mantle mucus' antimicrobial activity. Both PGN and LPS stress-induced alterations in amino acids, phospholipids, fatty acids, nucleotides, and their derivatives in the mantle. PGN injection activated the amino acid-related metabolism, and inhibited the lipid-related metabolisms in the mantle, while LPS injection activated the amino acid-related metabolisms and inhibited the arachidonic acid metabolism in the mantle compared to that in the control group. In addition, activation of the mTOR and FoxO signaling pathways and inhibition of lipid-related metabolism were observed in PGN vs. LPS. In addition, PGN injection induced the upregulation of fosfomycin and deoxynojirimycin in the mantle compared to LPS injection. Our study highlights the different responses at the metabolomic level of the mussel mantle to different MAMPs and the potential application of metabolites that specifically respond to PGN and LPS challenges in mussels as biomarkers.

The global COVID-19 pandemic caused by SARS-CoV-2 has underscored the urgent need for the development of new broad-spectrum antivirals to combat its high mutation rate and the emerging variants. Host ER α-glucosidases I/II are promising host-targeted therapeutic targets for the development of broad-spectrum antivirals against viral strains that depend on ERQC for infectivity. Herein, we designed and synthesized a series of TCM theory-inspired DNJ-flavonoid conjugates as novel α-glucosidase inhibitors, which were screened against their in vitro antiviral activities in non-replicative SARS-CoV-2 pseudovirus (PsV) assay. Remarkably, DNJ-20 not only demonstrated remarkable inhibition activity against α-glucosidase and viral entry process, but also exerted potent and broad-spectrum anti-coronaviral activity against SARS-CoV-2 pseudovirus (PsV), several SARS-CoV-2 variants, as well as HCoV-229E and HCoV-OC43, with EC₅₀ values up to 1.49 μM, which is more potent than the benchmark α-glucosidase inhibitor UV-4 (DNJ-3). Besides, it had no observable cytotoxicity in HeLa-ACE2, HEK-293T and Beas-2B cells. Therefore, TCM theory-inspired DNJ-flavonoid conjugates can be served as promising drug leads for pan-coronavirus therapeutic development to combat current and future coronavirus pandemics.