The Antiretroviral Agent Nelfinavir Mesylate.

Autor:	Sanchez, Cecilia G., Molinski, Steven V., Gongora, Rafael, Sosulski, Meredith, Fuselier, Taylor, MacKinnon, Stephen S., Mondal, Debasis, Lasky, Joseph A.
Předmět:	AUTOPHAGY ANIMAL experimentation BLEOMYCIN CARRIER proteins CELL differentiation CELLULAR signal transduction COLLAGEN COMPUTER simulation FAT cells FIBROBLASTS HIV infections LUNG injuries PULMONARY fibrosis SYSTEMIC scleroderma TRANSFORMING growth factors-beta NELFINAVIR PHARMACODYNAMICS THERAPEUTICS
Zdroj:	Arthritis & Rheumatology; Jan2018, Vol. 70 Issue 1, p115-126, 12p
Abstrakt:	Objective Transforming growth factor β1 ( TGFβ1) is considered a key factor in fibrogenesis, and blocking TGFβ1 signaling pathways diminishes fibrogenesis in animal models. The objective of this study was to determine whether nelfinavir mesylate ( NFV), a drug approved by the Food and Drug Administration ( FDA) for treating HIV infection, could be repurposed to treat pulmonary fibrosis in patients with systemic sclerosis ( SSc). Methods Normal human lung, ventricular, and skin fibroblasts as well as lung fibroblasts from SSc patients were used to determine the effects of NFV on fibroblast-to-myofibroblast differentiation mediated by TGFβ1. The efficacy of NFV was also evaluated in an animal model of SSc (bleomycin-induced pulmonary fibrosis). In addition, in silico analysis was performed to determine novel off-target effects of NFV. Results NFV inhibited TGFβ1-mediated fibroblast-to-myofibroblast differentiation in lung fibroblasts through inhibition of the TGFβ1 canonical pathway. NFV also inhibited differentiation of skin and ventricular fibroblasts and adipocyte precursors into myofibroblasts. Activation of the TGFβ1/mechanistic target of rapamycin pathway inhibited autophagy in lung fibroblasts, favoring collagen deposition, and NFV counteracted this effect in a dose-dependent manner. Moreover, NFV significantly reduced lung injury and collagen deposition in an animal model of SSc. In silico analysis of NFV binding proteins revealed new putative beneficial mechanisms of action, consistent with known common pathways in fibrogenesis. Conclusion NFV abrogates TGFβ1-mediated fibroblast-to-myofibroblast differentiation and pulmonary fibrosis through off-target protein binding, a finding that supports consideration of this FDA-approved medication as an antifibrotic agent. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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