The HIV Protease Inhibitor Saquinavir Inhibits HMGB1-Driven Inflammation by Targeting the Interaction of Cathepsin V with TLR4/MyD88

Molecular Medicine
John P PribisTimothy R Billiar

Abstract

Extracellular high-mobility group box 1 (HMGB1) (disulfide form), via activation of toll-like receptor 4 (TLR4)-dependent signaling, is a strong driver of pathologic inflammation in both acute and chronic conditions. Identification of selective inhibitors of HMGB1-TLR4 signaling could offer novel therapies that selectively target proximal endogenous activators of inflammation. A cell-based screening strategy led us to identify first generation HIV-protease inhibitors (PI) as potential inhibitors of HMGB1-TLR4 driven cytokine production. Here we report that the first-generation HIV-PI saquinavir (SQV), as well as a newly identified mammalian protease inhibitor STO33438 (334), potently block disulfide HMGB1-induced TLR4 activation, as assayed by the production of TNF-α by human monocyte-derived macrophages (THP-1). We further report on the identification of mammalian cathepsin V, a protease, as a novel target of these inhibitors. Cellular as well as recombinant protein studies show that the mechanism of action involves a direct interaction between cathepsin V with TLR4 and its adaptor protein MyD88. Treatment with SQV, 334 or the known cathepsin inhibitor SID26681509 (SID) significantly improved survival in murine models of sepsi...Continue Reading

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Citations

Aug 23, 2019·Glia·María Velasco-EstevezGraham K Sheridan
May 2, 2020·The European Journal of Neuroscience·Chloe M HallGraham K Sheridan
Dec 10, 2019·Cancer Immunology, Immunotherapy : CII·Tanja JakošJanko Kos
Mar 7, 2021·International Journal of Molecular Sciences·Rita MorettiClaudio Tiribelli
Jul 3, 2017·Trends in Pharmacological Sciences·Lovro KramerBoris Turk
Jun 27, 2020·ACS Chemical Neuroscience·Jeremy D BakerBrian C Kraemer

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