DOI: 10.1101/2023.05.22.541802

Novel TRPM7 inhibitors with potent anti-inflammatory effects in vivo

G. W.Busey M. C. Manjegowda T. Huang W. H. Iobst S. S. Naphade J. A. Kennedy C. A. Doyle P. V. Seegren K. R. Lynch B. N. Desai

G. W.Busey M. C. Manjegowda T. Huang ...+6 B. N. Desai

摘要

TRPM7, a TRP channel with ion conductance and kinase activities, has emerged as an attractive drug target for immunomodulation. Reverse genetics and cell biological studies have established a key role for TRPM7 in the inflammatory activation of macrophages. Advancing TRPM7 as a viable molecular target for immunomodulation requires selective TRPM7 inhibitors with in vivo tolerability and efficacy. Such inhibitors have the potential to interdict inflammatory cascades mediated by systemic and tissue-specialized macrophages. FTY720, an FDA-approved drug for multiple sclerosis inhibits TRPM7. However, FTY720 is a prodrug and its metabolite, FTY720-phosphate, is a potent agonist of sphingosine 1-phosphate (S1P) receptors. In this study, we tested nonphosphorylatable FTY720 analogs, which are inert against S1PRs and well tolerated in vivo, for activity against TRPM7 and tissue bioavailability. Using patch clamp electrophysiology, we show that VPC01091.4 and AAL-149 block TRPM7 current at low micromolar concentrations and can act directly on macrophages to blunt LPS-induced inflammatory cytokine expression. We found that VPC01091.4 has significant and rapid accumulation in the brain and lungs, along with direct anti-inflammatory action on alveolar macrophages and microglia. Finally, using a mouse model of endotoxemia, we show VPC01091.4 to be an efficacious anti-inflammatory agent that arrests systemic inflammation in vivo. Together, these findings reveal a promising new class of anti-inflammatory TRPM7 inhibitors, setting the stage for preclinical evaluation in various immunopathologies.

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