The identification of novel small molecules that can target endogenous factors to regulate β-cell proliferation is a desirable goal to counter all forms of diabetes. Recently, we identified serpinB1 (SB1), an endogenous protease inhibitor, as a protein that promotes human β-cell proliferation by inhibiting elastase activity, and demonstrated that the elastase inhibitor sivelestat also induced β-cell proliferation. Here, we report high-throughput screening to identify novel elastase inhibitors and to evaluate their ability to induce human β-cell proliferation. We screened 16,320 compounds using a fluorescence-based porcine pancreatic elastase (pPE) assay, and confirmed inhibition of human neutrophil (hNE) and pancreatic (hPE) elastases using an absorbance-based assay. We observed that telaprevir and tebipenem each inhibited pPE with greater potency than sivelestat (IC50: telaprevir 33.9 nM, tebipenem 1.1 µM, sivelestat 2.4 µM; n=3). The results were confirmed on hPE (IC50: telaprevir 15.7 nM, tebipenem 3.6, sivelestat 2.3 µM; n=3), while neither telaprevir nor tebipenem blocked hNE activity. Interestingly, telaprevir and SB1 inhibited hPE and pPE at similar concentrations, enforcing the hypothesis of a shared mechanism of action between the protein and the compound. We then assessed the mitogenic properties of the compounds in in vitro cultures of mouse and human islets by immunofluorescence. Telaprevir and tebipenem each increased proliferating β-cells in rodent (∼6-fold and 1.5-fold increase, respectively; n=3) and human islets (∼4-fold and 1.5-fold increase, respectively; n=3) compared to vehicle-treated islets. Taken together, these data confirm the identification of two novel compounds with the ability to inhibit pancreatic elastase and enhance mammalian β-cell proliferation. These results highlight the therapeutic potential of using elastase inhibitors to stimulate β-cell proliferation to treat diabetes.


G. Basile: None. A. Vetere: None. J. Hu: None. B. Wagner: None. R. Kulkarni: None.

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