Evaluating Z-FA-FMK, a host cathepsin L protease inhibitor, as a potent and broad-spectrum antiviral therapy against SARS-CoV-2 and related coronaviruses

Jeong, Ju Hwan; Choi, Jang‐Hoon; Kim, Beom Kyu; Min, Seong Cheol; Chokkakula, Santosh; Oh, Sol; Park, Jihyun; Shim, Sang-Mu; Kim, Eung‐Gook; Choi, Young Ki; Lee, Joo-Yeon; Baek, Yun Hee; Song, Min‐Suk

doi:10.1016/j.antiviral.2023.105669

Cited by 4 publications

(3 citation statements)

References 41 publications

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“…24,25 The fluoromethylketone Z-FA-FMK, a potent, irreversible inhibitor of a number of cysteine proteases, including cathepsins B, L, and S, with less pronounced activity against M pro , 31 has demonstrated excellent anti-SARS-CoV-2 activity in vitro and in vivo. 32 Moreover, the strong cathepsin inhibitor calpeptin, a Z-protected leucine-norleucine-derived aldehyde, was active in SARS-CoV-2-treated hamsters. 33 The growing appeal of cathepsins as therapeutic targets for COVID-19 served as the impetus for our research.…”

Section: Introductionmentioning

confidence: 99%

Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological Activity

Flury,

Breidenbach,

Krüger

et al. 2023

Preprint

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Cathepsins (Cats) are proteases that mediate the successful entry of SARS-CoV-2 into host cells. We designed and synthesized a tailored series of 21 peptidomimetics and evaluated their inhibitory activity against human cathepsins L, B, and S. Structural diversity was realized by combinations of different C-terminal warhead functions and N-terminal capping groups, while a central Leu-Phe fragment was maintained. Several compounds were identified as promising cathepsin L and S inhibitors with Ki values in the low nanomolar to subnanomolar range, for example, the peptide aldehydes 9a and 9b (9a, 2.67 nM, CatL; 0.0455 nM, CatS; 9b, 1.76 nM, CatL; 0.0512 nM, CatS). The compounds’ inhibitory activity against the main protease of SARS-CoV-2 (Mpro) was additionally investigated. Based on the results at CatL, CatS, and Mpro, selected inhibitors were subjected to investigations of their antiviral activity in cell-based assays. In particular, the peptide nitrile 11e exhibited promising antiviral activity with an EC50 value of 35.1 nM in Calu-3 cells without showing cytotoxicity. High metabolic stability and favorable pharmacokinetic properties make 11e suitable for further preclinical development.

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Section: Introductionmentioning

confidence: 99%

Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological Activity

Flury,

Breidenbach,

Krüger

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…27,28 The fluoromethylketone Z-FA-FMK, a potent, irreversible inhibitor of a number of cysteine proteases, including cathepsins B, L, and S, with less pronounced activity against M pro , 34 has demonstrated excellent anti-SARS-CoV-2 activity in vitro and in vivo. 35 Moreover, the strong cathepsin inhibitor calpeptin, a Z-protected leucine-norleucine-derived aldehyde, was active in SARS-CoV-2-treated hamsters. 36 The growing appeal of cathepsins as therapeutic targets for COVID-19 served as the impetus for our research.…”

mentioning

confidence: 99%

“…The highly potent CatS/L inhibitor K777 and the picomolar cathepsin L inhibitor gallinamide A reduced SARS-CoV-2 infections in a number of cell lines. Both K777 and gallinamide A were inactive against M pro . , The fluoromethylketone Z-FA-FMK, a potent, irreversible inhibitor of a number of cysteine proteases, including cathepsins B, L, and S, with less pronounced activity against M pro , has demonstrated excellent anti-SARS-CoV-2 activity in vitro and in vivo . Moreover, the strong cathepsin inhibitor calpeptin, a Z-protected leucine-norleucine-derived aldehyde, was active in SARS-CoV-2-treated hamsters …”

mentioning

confidence: 99%

Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological Activity

Flury,

Breidenbach,

Krüger

et al. 2024

ACS Pharmacol. Transl. Sci.

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Cathepsins (Cats) are proteases that mediate the successful entry of SARS-CoV-2 into host cells. We designed and synthesized a tailored series of 21 peptidomimetics and evaluated their inhibitory activity against human cathepsins L, B, and S. Structural diversity was realized by combinations of different C-terminal warhead functions and N-terminal capping groups, while a central Leu-Phe fragment was maintained. Several compounds were identified as promising cathepsin L and S inhibitors with K i values in the low nanomolar to subnanomolar range, for example, the peptide aldehydes 9a and 9b (9a, 2.67 nM, CatL; 0.455 nM, CatS; 9b, 1.76 nM, CatL; 0.512 nM, CatS). The compounds' inhibitory activity against the main protease of SARS-CoV-2 (M pro ) was additionally investigated. Based on the results at CatL, CatS, and M pro , selected inhibitors were subjected to investigations of their antiviral activity in cell-based assays. In particular, the peptide nitrile 11e exhibited promising antiviral activity with an EC 50 value of 38.4 nM in Calu-3 cells without showing cytotoxicity. High metabolic stability and favorable pharmacokinetic properties make 11e suitable for further preclinical development.

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Establishment, optimization and validation of a fluorescence polarization-based high-throughput screening assay targeting cathepsin L inhibitors

Zhou,

You,

Zhao

et al. 2024

SLAS Discovery

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Evaluating Z-FA-FMK, a host cathepsin L protease inhibitor, as a potent and broad-spectrum antiviral therapy against SARS-CoV-2 and related coronaviruses

Cited by 4 publications

References 41 publications

Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological Activity

Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological Activity

Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological Activity

Establishment, optimization and validation of a fluorescence polarization-based high-throughput screening assay targeting cathepsin L inhibitors

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