In vitro testing of host-targeting small molecule antiviral matriptase/TMPRSS2 inhibitors in 2D and 3D cell-based assays

van Eijk, Nicholas; Schmacke, Luna C.; Steinmetzer, Torsten; Pilgram, Oliver; Poór, Miklós; Pászti-Gere, Erzsébet

doi:10.1016/j.biopha.2023.115761

Cited by 3 publications

(1 citation statement)

References 53 publications

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“…Host-targeting antivirals, such as T-705 (favipiravir) and remdesivir, show potential against Marburg virus through preclinical investigations ( Alsaady et al, 2023 ; Srivastava et al, 2023 ). However, no licensed medical countermeasures are available, necessitating further research and clinical trials for effective treatment development ( Kortepeter et al, 2020 ; van Eijk et al, 2023 ). Interferons and interferon stimulators are under investigation for Marburg virus treatment, considering the virus’s evasion of interferon responses.…”

Section: Exploring Molecular Targets and Therapeutic Approachesmentioning

confidence: 99%

Novel antiviral approaches for Marburg: a promising therapeutics in the pipeline

Srivastava,

Kumar,

Ashique

et al. 2024

Front. Microbiol.

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Marburg virus disease (MVD) presents a significant global health threat, lacking effective antivirals and with current supportive care offering limited therapeutic options. This mini review explores the emerging landscape of novel antiviral strategies against MVD, focusing on promising therapeutics currently in the development pipeline. We delve into direct-acting antiviral approaches, including small molecule inhibitors targeting viral entry, replication, and assembly, alongside nucleic acid antisense and RNA interference strategies. Host-targeting antivirals are also considered, encompassing immune modulators like interferons and cytokine/chemokine modulators, broad-spectrum antivirals, and convalescent plasma and antibody-based therapies. The paper then examines preclinical and clinical development for the novel therapeutics, highlighting in vitro and in vivo models for antiviral evaluation, safety and efficacy assessments, and the critical stages of clinical trials. Recognizing the challenges of drug resistance and viral escape, the mini review underscores the potential of combination therapy strategies and emphasizes the need for rapid diagnostic tools to optimize treatment initiation. Finally, we discuss the importance of public health preparedness and equitable access to these promising therapeutics in achieving effective MVD control and global health security. This mini review presents a comprehensive overview of the burgeoning field of MVD antivirals, highlighting the potential of these novel approaches to reshape the future of MVD treatment and prevention.

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Section: Exploring Molecular Targets and Therapeutic Approachesmentioning

confidence: 99%

Novel antiviral approaches for Marburg: a promising therapeutics in the pipeline

Srivastava,

Kumar,

Ashique

et al. 2024

Front. Microbiol.

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PK/PD investigation of antiviral host matriptase/TMPRSS2 inhibitors in cell models

Gamba,

van Eijk,

Lányi

et al. 2024

Sci Rep

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Certain corona- and influenza viruses utilize type II transmembrane serine proteases for cell entry, making these enzymes potential drug targets for the treatment of viral respiratory infections. In this study, the cytotoxicity and inhibitory effects of seven matriptase/TMPRSS2 inhibitors (MI-21, MI-463, MI-472, MI-485, MI-1900, MI-1903, and MI-1904) on cytochrome P450 enzymes were evaluated using fluorometric assays. Additionally, their antiviral activity against influenza A virus subtypes H1N1 and H9N2 was assessed. The metabolic depletion rates of these inhibitors in human primary hepatocytes were determined over a 120-min period by LC–MS/MS, and PK parameters were calculated. The tested compounds, with the exception of MI-21, displayed potent inhibition of CYP3A4, while all compounds lacked inhibitory effects on CYP1A2, CYP2C9, CYP2C19, and CYP2D6. The differences between the CYP3A4 activity within the series were rationalized by ligand docking. Elucidation of PK parameters showed that inhibitors MI-463, MI-472, MI-485, MI-1900 and MI-1904 were more stable compounds than MI-21 and MI-1903. Anti-H1N1 properties of inhibitors MI-463 and MI-1900 and anti-H9N2 effects of MI-463 were shown at 20 and 50 µM after 24 h incubation with the inhibitors, suggesting that these inhibitors can be applied to block entry of these viruses by suppressing host matriptase/TMPRSS2-mediated cleavage.

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Quercetin and taxifolin inhibits TMPRSS2 activity and its interaction with EGFR in paclitaxel‐resistant breast cancer cells: An in silico and in vitro study

Kundrapu,

Chaitanya,

Manaswi

et al. 2024

Chem Biol Drug Des

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Transmembrane protease/serine (TMPRSS2), a type II transmembrane serine protease, plays a crucial role in different stages of cancer. Recent studies have reported that the triggering epidermal growth factor receptor (EGFR) activation through protease action promotes metastasis. However, there are no reports on the interaction of TMPRSS2 with EGFR, especially in triple‐negative triple negative (TNBC). The current study investigates the unexplored interaction between TMPRSS2 and EGFR, which are key partners mediating metastasis. This interaction is explored for potential targeting using quercetin (QUE) and taxifolin (TAX). TMPRSS2 expression patterns in breast cancer (BC) tissues and subtypes have been predicted, with the prognostic significance assessed using the GENT2.0 database. Validation of TMPRSS2 expression was performed in normal and TNBC tissues, including drug‐resistant cell lines, utilizing GEO datasets. TMPRSS2 was further validated as a predictive biomarker for FDA‐approved chemotherapeutics through transcriptomic data from BC patients. The study demonstrated the association of TMPRSS2 with EGFR through in silico analysis and validates the findings in TNBC cohorts using the TIMER2.0 web server and the TCGA dataset through C‐Bioportal. Molecular docking and molecular dynamic simulation studies identified QUE and TAX as best leads targeting TMPRSS2. They inhibited cell‐free TMPRSS2 activity like clinical inhibitor of TMPRSS2, Camostat mesylate. In cell‐based assays focused on paclitaxel‐resistant TNBC (TNBC/PR), QUE and TAX demonstrated potent inhibitory activity against extracellular and membrane‐bound TMPRSS2, with low IC50 values. Furthermore, ELISA and cell‐based AlphaLISA assays demonstrated that QUE and TAX inhibit the interaction of TMPRSS2 with EGFR. Additionally, QUE and TAX exhibited significant inhibition of proliferation and cell cycle accompanied by notable alterations in the morphology of TNBC/PR cells. This study provides valuable insights into potential of QUE and TAX targeting TMPRSS2 overexpressing TNBC.

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In vitro testing of host-targeting small molecule antiviral matriptase/TMPRSS2 inhibitors in 2D and 3D cell-based assays

Cited by 3 publications

References 53 publications

Novel antiviral approaches for Marburg: a promising therapeutics in the pipeline

Novel antiviral approaches for Marburg: a promising therapeutics in the pipeline

PK/PD investigation of antiviral host matriptase/TMPRSS2 inhibitors in cell models

Quercetin and taxifolin inhibits TMPRSS2 activity and its interaction with EGFR in paclitaxel‐resistant breast cancer cells: An in silico and in vitro study

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