Design, synthesis, and biological evaluation of first-in-class indomethacin-based PROTACs degrading SARS-CoV-2 main protease and with broad-spectrum antiviral activity

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 268, С. 116202 - 116202

Опубликована: Фев. 6, 2024

To date, Proteolysis Targeting Chimera (PROTAC) technology has been successfully applied to mediate proteasomal-induced degradation of several pharmaceutical targets mainly related oncology, immune disorders, and neurodegenerative diseases. On the other hand, its exploitation in field antiviral drug discovery is still infancy. Recently, we described two indomethacin (INM)-based PROTACs displaying broad-spectrum activity against coronaviruses. Here, report design, synthesis, characterization a novel series INM-based that recruit either Von-Hippel Lindau (VHL) or cereblon (CRBN) E3 ligases. The panel was also enlarged by varying linker moiety. resulted very susceptible this modification, particularly for hijacking VHL as ligase, with one piperazine-based compound (PROTAC 6) showing potent anti-SARS-CoV-2 infected human lung cells. Interestingly, assays both uninfected virus-infected cells most promising emerged so far (PROTACs 5 demonstrated INM-PROTACs do not degrade PGES-2 protein, initially hypothesized, but induce concentration-dependent SARS-CoV-2 main protease (Mpro) Mpro-transfected SARS-CoV-2-infected Importantly, thanks target degradation, exhibited considerable enhancement respect indomethacin, EC50 values low-micromolar/nanomolar range. Finally, kinetic solubility well metabolic chemical stability were measured 6. Altogether, identification first class Mpro degraders demonstrating represents significant advance development effective, anti-coronavirus strategies.

Язык: Английский

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Synthesis, biological evaluation and molecular docking studies of flavonol-3-O-β-D-glycoside as a potential inhibitor of SARS-CoV-2 main protease (3CLpro) in drug development for COVID-19

International Journal of Biological Macromolecules, Год журнала: 2025, Номер unknown, С. 139621 - 139621

Опубликована: Янв. 1, 2025

Язык: Английский

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Effects of organic salts of virucidal and antiviral compounds from Nelumbo nucifera and Kaempferia parviflora against SARS-CoV-2

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Фев. 21, 2025

The present work investigates virucidal and antiviral compounds in the extracts of seed embryos a lotus, Nelumbo nucifera, Thai ginseng, Kaempferia parviflora. Separation led to identification against SARS-CoV-2. Neferine (1) nuciferine (3) from N. as well their respective HCl salts (2 4), exhibited activities Virucidal activity neferine salt (2) (EC50 4.78 µM) was 7.5 times better than its free-base, 36.01 µM), also improved selectivity index (SI), showing less cytotoxicity 1. This demonstrates that organic have an impact on biological activities. A crude extract K. parviflora rhizomes displayed 42.11 µg/mL) 39.28 µg/mL). Isolation nine flavonoids (5–13). Among these flavonoids, only 5,7,4'-trimethoxyflavone (8) found show 437.90 50.97 However, (5–13) did not inhibit SARS-CoV-2 3CLpro enzyme at concentrations 10 µM 100 µM. In conclusion, our data underscores therapeutic potential nucifera derived bioactive

Язык: Английский

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Development of Peptidomimetic PROTACs as Potential Degraders of 3-Chymotrypsin-like Protease of SARS-CoV-2

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(8), С. 3903 - 3903

Опубликована: Апрель 21, 2025

3CL protease (3CLpro), a key enzyme of SARS-CoV-2 replication, is one the most selective targets antivirals, as no homologous has been recognized in human body. As proteolysis-targeting chimeras (PROTACs) are superior to traditional inhibitors, based on reported cereblon (CRBN) ligands thalidomide and lenalidomide, 3CLpro peptidomimetic suitable linkers, we aimed develop novel PROTACs that may trigger efficient intracellular degradation through balance hydrophilicity lipophilicity. In brief, designed synthesized 5 PROTAC molecules. The efficiency was assayed stable expression HEK293 cell models evaluated by Western blot. All compounds showed prominent activity with tolerable cytotoxicity. compounds, 15 16, have DC50 values approximately 1 µM, Dmax 89.3% 75% respectively, indicating good potential for further application.

Язык: Английский

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A Gaussia luciferase reporter assay for the evaluation of coronavirus Nsp5/3CLpro activity

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Сен. 5, 2024

Язык: Английский

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Enantioselective Reductive Cyclization of Alkynyl-Tethered Cyclohexadienones Catalyzed by Rhodium Complexes

Organic Letters, Год журнала: 2024, Номер 26(27), С. 5614 - 5619

Опубликована: Июль 2, 2024

Although various types of asymmetric cyclization reactions 1,6-enynes have been established, simple reductive remains underdeveloped. In this study, the enantioselective alkynyl-tethered cyclohexadienones (1,6-enynes) has developed via a chiral pincer rhodium catalyst, affording

Язык: Английский

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How many organic small molecules might be used to treat COVID-19? From natural products to synthetic agents

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 278, С. 116788 - 116788

Опубликована: Сен. 4, 2024

Язык: Английский

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Molecular Insights into Structural Dynamics and Binding Interactions of Selected Inhibitors Targeting SARS-CoV-2 Main Protease

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(24), С. 13482 - 13482

Опубликована: Дек. 16, 2024

The SARS-CoV-2 main protease (Mpro, also known as 3CLpro) is a key target for antiviral therapy due to its critical role in viral replication and maturation. This study investigated the inhibitory effects of Bofutrelvir, Nirmatrelvir, Selinexor on 3CLpro through molecular docking, dynamics (MD) simulations, free energy calculations. Nirmatrelvir exhibited strongest binding affinity across docking tools (AutoDock Vina: -8.3 kcal/mol; DiffDock: -7.75 DynamicBound: 7.59 7.89 kcal/mol), outperforming Bofutrelvir. Triplicate 300 ns MD simulations revealed that Nirmatrelvir-3CLpro complex displayed high conformational stability, reduced root mean square deviation (RMSD), modest decrease solvent-accessible surface area (SASA), indicating enhanced structural rigidity. Gibbs analysis highlighted greater flexibility unbound 3CLpro, stabilized by binding, supported stable hydrogen bonds. MolProphet prediction tools, targeting Cys145 residue, confirmed forming multiple hydrophobic, hydrogen, π-stacking interactions with residues, had lowest predicted IC50/EC50 (9.18 × 10-8 mol/L), superior potency. Bofutrelvir showed weaker higher values. MM/PBSA calculated -100.664 ± 0.691 kJ/mol complex, further supporting stability These results underscore Nirmatrelvir's potential promising therapeutic agent provide novel insights into dynamic stabilizing AI-based long-term simulations.

Язык: Английский

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A Gaussia luciferase reporter assay for the evaluation of coronavirus Nsp5/3CLpro inhibitors

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Май 23, 2024

Human coronaviruses (hCoVs) infect millions of people every year. Among these, MERS, SARS-CoV-1, and SARS-CoV-2 caused significant morbidity mortality their emergence highlights the risks associated with possible future coronavirus outbreaks. Therefore, broadly-active anti-coronavirus drugs are needed. Pharmacological inhibition hCoV protease 3CLpro (Nsp5) in COVID-19 patients is clinically beneficial as shown by wide effective use Paxlovid (nirmaltrevir, ritonavir). However, further treatment options required due to drug resistance some strains. To facilitate inhibitor discovery evaluation, we developed an assay allowing rapid reliable quantification activity under biosafety level 1 conditions. It based on ACE2 receptor - Gal4 transcription factor fusion protein separated a recognition site. Cleavage releases factor, which then induces expression Gaussia luciferase. Our compatible proteases from all hCoVs, allows simultaneous measurement inhibitory cytotoxic effects tested compounds. Proof-of-concept IC₅₀ measurements confirmed that nirmaltrevir, GC376 lopinavir inhibit function without inducing cytotoxicity. Overall, luciferase-based reporter suitable for evaluating viral screening potential inhibitors.

Язык: Английский

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Inhibition of SARS-CoV-2 3CLpro by chemically modified tyrosinase from Agaricus bisporus

RSC Medicinal Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Янв. 1, 2024

A novel antiviral and non-cytotoxic bioconjugate of tyrosinase from Agaricus bisporus (AbTyr)-dextran-aspartic acid (6 kDa) polymer is developed.

Язык: Английский

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