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

---

On the origins of SARS-CoV-2 main protease inhibitors

RSC Medicinal Chemistry, Год журнала: 2023, Номер 15(1), С. 81 - 118

Опубликована: Окт. 13, 2023

In order to address the world-wide health challenge caused by COVID-19 pandemic, 3CL protease/SARS-CoV-2 main protease (SARS-CoV-2-M

Язык: Английский

---

Terminalia chebula Retz. aqueous extract inhibits the Helicobacter pylori-induced inflammatory response by regulating the inflammasome signaling and ER-stress pathway

Journal of Ethnopharmacology, Год журнала: 2023, Номер 320, С. 117428 - 117428

Опубликована: Ноя. 18, 2023

Язык: Английский

---

Synthesis and biological evaluation of novel peptidomimetic inhibitors of the coronavirus 3C-like protease

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 268, С. 116263 - 116263

Опубликована: Фев. 24, 2024

Язык: Английский

---

Structure-based design of SARS-CoV-2 papain-like protease inhibitors

European Journal of Medicinal Chemistry, Год журнала: 2023, Номер 264, С. 116011 - 116011

Опубликована: Дек. 5, 2023

Язык: Английский

---

Design, Synthesis, X-ray Crystallography, and Biological Activities of Covalent, Non-Peptidic Inhibitors of SARS-CoV-2 Main Protease

ACS Infectious Diseases, Год журнала: 2024, Номер 10(2), С. 715 - 731

Опубликована: Янв. 9, 2024

Highly contagious SARS-CoV-2 coronavirus has infected billions of people worldwide with flu-like symptoms since its emergence in 2019. It caused deaths several million people. The viral main protease (Mpro) is essential for replication and therefore a drug target. Several series covalent inhibitors Mpro were designed synthesized. Structure-activity relationship studies show that (1) chloroacetamide- epoxide-based compounds targeting Cys145 are potent IC50 values as low 0.49 μM (2) Cys44 not nucleophilic inhibitor design. High-resolution X-ray revealed the protein-inhibitor interactions mechanisms inhibition. interest preferably attacks more hindered Cα atom epoxide inhibitors. Chloroacetamide 13 30 found to inhibit cellular an EC68 (half-log reduction virus titer) 3 5 μM. These represent new pharmacological leads anti-SARS-CoV-2 development.

Язык: Английский

---

Targeting SARS-CoV-2 nonstructural protein 3: Function, structure, inhibition, and perspective in drug discovery

Drug Discovery Today, Год журнала: 2023, Номер 29(1), С. 103832 - 103832

Опубликована: Ноя. 16, 2023

Язык: Английский

---

Synthesis and biological investigation of peptidomimetic SARS‐CoV‐2 main protease inhibitors bearing quinoline‐based heterocycles at P₃

Archiv der Pharmazie, Год журнала: 2025, Номер 358(1)

Опубликована: Янв. 1, 2025

Abstract In the last few years, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has been cause of a worldwide pandemic, highlighting need for novel antiviral agents. The main protease (M pro ) SARS‐CoV‐2 was immediately identified as crucial enzyme viral replication and validated drug target. Here, we present design synthesis peptidomimetic M covalent inhibitors characterized by quinoline‐based P 3 moieties. Structure–activity relationships (SARs) were also investigated at 1 , well different warheads. binding modes designed assessed using X‐ray crystallographic molecular docking studies. tested their activities in cell‐based assays, results encouraging. SAR studies presented here can contribute to future improved addressing some current or prospective issues regarding currently used therapy.

Язык: Английский

---

In Silico Tuning of Binding Selectivity for New SARS-CoV-2 Main Protease Inhibitors

Computer Methods and Programs in Biomedicine, Год журнала: 2025, Номер 262, С. 108678 - 108678

Опубликована: Фев. 18, 2025

Язык: Английский

---

Inhibitory efficacy and structural insights of Bofutrelvir against SARS-CoV-2 Mpro mutants and MERS-CoV Mpro

Communications Biology, Год журнала: 2025, Номер 8(1)

Опубликована: Март 25, 2025

The COVID-19 pandemic has caused significant global health and economic disruption. Mutations E166N, E166R, S144A His163A in the SARS-CoV-2 main protease (Mpro) have been implicated reducing efficacy of certain antiviral treatments. Bofutrelvir, a promising inhibitor, shown effectiveness against Mpro. This study aims to evaluate inhibitory effects Bofutrelvir on His163A, E166V mutants Mpro, as well MERS-CoV Our findings indicate substantial reduction potency these MERS-CoV, with IC50 values significantly higher than those for wild-type Specifically, E166V, S144A, H163A mutations reduce binding affinity due disrupted hydrogen bonds, altered site stability, reduced enzyme activity. Structural analysis crystal complexes showed that changes interactions at S1 subsite loss bonds S4 Mpro are critical factors contributing diminished These insights reveal necessity ongoing structural adapt therapeutic strategies. (E166N/R/V, H163A) by disrupting destabilizing pockets, altering enzymatic

Язык: Английский

---