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Research ArticleDrug Discovery and Translational Medicine

Inhibiting Sialidase-Induced TGF-β1 Activation Attenuates Pulmonary Fibrosis in Mice

Tejas R. Karhadkar, Thomas D. Meek and Richard H. Gomer
Journal of Pharmacology and Experimental Therapeutics January 2021, 376 (1) 106-117; DOI: https://doi.org/10.1124/jpet.120.000258
Tejas R. Karhadkar
Departments of Biology (T.R.K., R.H.G.) and Biochemistry and Biophysics (T.D.M.), Texas A&M University, College Station, Texas
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Thomas D. Meek
Departments of Biology (T.R.K., R.H.G.) and Biochemistry and Biophysics (T.D.M.), Texas A&M University, College Station, Texas
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Richard H. Gomer
Departments of Biology (T.R.K., R.H.G.) and Biochemistry and Biophysics (T.D.M.), Texas A&M University, College Station, Texas
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Abstract

The active form of transforming growth factor-β1 (TGF-β1) plays a key role in potentiating fibrosis. TGF-β1 is sequestered in an inactive state by a latency-associated glycopeptide (LAP). Sialidases (also called neuraminidases (NEU)) cleave terminal sialic acids from glycoconjugates. The sialidase NEU3 is upregulated in fibrosis, and mice lacking Neu3 show attenuated bleomycin-induced increases in active TGF-β1 in the lungs and attenuated pulmonary fibrosis. Here we observe that recombinant human NEU3 upregulates active human TGF-β1 by releasing active TGF-β1 from its latent inactive form by desialylating LAP. Based on the proposed mechanism of action of NEU3, we hypothesized that compounds with a ring structure resembling picolinic acid might be transition state analogs and thus possible NEU3 inhibitors. Some compounds in this class showed nanomolar IC50 for recombinant human NEU3 releasing active human TGF-β1 from the latent inactive form. The compounds given as daily 0.1–1-mg/kg injections starting at day 10 strongly attenuated lung inflammation, lung TGF-β1 upregulation, and pulmonary fibrosis at day 21 in a mouse bleomycin model of pulmonary fibrosis. These results suggest that NEU3 participates in fibrosis by desialylating LAP and releasing TGF-β1 and that the new class of NEU3 inhibitors are potential therapeutics for fibrosis.

SIGNIFICANCE STATEMENT The extracellular sialidase NEU3 appears to be a key driver of pulmonary fibrosis. The significance of this report is that 1) we show the mechanism (NEU3 desialylates the latency-associated glycopeptide protein that keeps the profibrotic cytokine transforming growth factor-β1 (TGF-β1) in an inactive state, causing active TGF-β1 release), 2) we then use the predicted NEU3 mechanism to identify nM IC50 NEU3 inhibitors, and 3) these new NEU3 inhibitors are potent therapeutics in a mouse model of pulmonary fibrosis.

Footnotes

    • Received July 30, 2020.
    • Accepted October 6, 2020.
  • This work was supported by National Institutes of Health National Heart, Lung, and Blood Institute [Grant R01 HL132919]. T.R.K., T.D.M., and R.H.G. are inventors on a patent application for the use of this class of sialidase inhibitors as therapeutics for a variety of diseases.

  • https://doi.org/10.1124/jpet.120.000258.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 1
1 Jan 2021
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Research ArticleDrug Discovery and Translational Medicine

Sialidase-Induced TGF-β1 Activation and Fibrosis

Tejas R. Karhadkar, Thomas D. Meek and Richard H. Gomer
Journal of Pharmacology and Experimental Therapeutics January 1, 2021, 376 (1) 106-117; DOI: https://doi.org/10.1124/jpet.120.000258

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Research ArticleDrug Discovery and Translational Medicine

Sialidase-Induced TGF-β1 Activation and Fibrosis

Tejas R. Karhadkar, Thomas D. Meek and Richard H. Gomer
Journal of Pharmacology and Experimental Therapeutics January 1, 2021, 376 (1) 106-117; DOI: https://doi.org/10.1124/jpet.120.000258
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