The HIV protease inhibitor saquinavir inhibits HMGB1-driven inflammation by targeting the interaction of cathepsin V with TLR4/MyD88

John P. Pribis, Yousef Al-Abed, Huan Yang, Domokos Gero, Hongbo Xu, Marcelo F. Montenegro, Eileen M. Bauer, Sodam Kim, Sangeeta S. Chavan, Changchun Cai, Tunliang Li, Petra Szoleczky, Csaba Szabo, Kevin J. Tracey, Timothy R. Billiar

Research output: Contribution to journalArticle

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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 macro-phages (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 sepsis and reduced liver damage following warm liver ischemia/reperfusion (I/R) models, both characterized by strong HMGB1-TLR4 driven pathology. The current study demonstrates a novel role for cathepsin V in TLR4 signaling and implicates cathepsin V as a novel target for first-generation HIV-PI compounds. The identification of cathepsin V as a target to block HMGB1-TLR4-driven inflammation could allow for a rapid transition of the discovery from the bench to the bedside. Disulfide HMGB1 drives pathologic inflammation in many models by activating signaling through TLR4. Cell-based screening identified the mammalian protease cathepsin V as a novel therapeutic target to inhibit TLR4-mediated inflammation induced by extracellular HMGB1 (disulfide form). We identified two protease inhibitors (PIs) that block cathepsin V and thereby inhibit disulfide HMGB1-induced TLR4 activation: saquinavir (SQV), a firstgeneration PI targeting viral HIV protease and STO33438 (334), targeting mammalian proteases. We discovered that cathepsin V binds TLR4 under basal and HMGB1-stimulated conditions, but dissociates in the presence of SQV over time. Thus cathepsin V is a novel target for first-generation HIV PIs and represents a potential therapeutic target of pathologic inflammation.

Original languageEnglish (US)
Pages (from-to)749-757
Number of pages9
JournalMolecular Medicine
Volume21
DOIs
StatePublished - Aug 24 2015

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Saquinavir
HIV Protease Inhibitors
Cathepsins
Toll-Like Receptor 4
Inflammation
Disulfides
Protease Inhibitors
Myeloid Differentiation Factor 88
HIV Protease
Warm Ischemia
Liver
Recombinant Proteins
Bacteriophages
Reperfusion
Monocytes

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

The HIV protease inhibitor saquinavir inhibits HMGB1-driven inflammation by targeting the interaction of cathepsin V with TLR4/MyD88. / Pribis, John P.; Al-Abed, Yousef; Yang, Huan; Gero, Domokos; Xu, Hongbo; Montenegro, Marcelo F.; Bauer, Eileen M.; Kim, Sodam; Chavan, Sangeeta S.; Cai, Changchun; Li, Tunliang; Szoleczky, Petra; Szabo, Csaba; Tracey, Kevin J.; Billiar, Timothy R.

In: Molecular Medicine, Vol. 21, 24.08.2015, p. 749-757.

Research output: Contribution to journalArticle

Pribis, JP, Al-Abed, Y, Yang, H, Gero, D, Xu, H, Montenegro, MF, Bauer, EM, Kim, S, Chavan, SS, Cai, C, Li, T, Szoleczky, P, Szabo, C, Tracey, KJ & Billiar, TR 2015, 'The HIV protease inhibitor saquinavir inhibits HMGB1-driven inflammation by targeting the interaction of cathepsin V with TLR4/MyD88', Molecular Medicine, vol. 21, pp. 749-757. https://doi.org/10.2119/molmed.2015.00197
Pribis, John P. ; Al-Abed, Yousef ; Yang, Huan ; Gero, Domokos ; Xu, Hongbo ; Montenegro, Marcelo F. ; Bauer, Eileen M. ; Kim, Sodam ; Chavan, Sangeeta S. ; Cai, Changchun ; Li, Tunliang ; Szoleczky, Petra ; Szabo, Csaba ; Tracey, Kevin J. ; Billiar, Timothy R. / The HIV protease inhibitor saquinavir inhibits HMGB1-driven inflammation by targeting the interaction of cathepsin V with TLR4/MyD88. In: Molecular Medicine. 2015 ; Vol. 21. pp. 749-757.
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AU - Pribis, John P.

AU - Al-Abed, Yousef

AU - Yang, Huan

AU - Gero, Domokos

AU - Xu, Hongbo

AU - Montenegro, Marcelo F.

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N2 - 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 macro-phages (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 sepsis and reduced liver damage following warm liver ischemia/reperfusion (I/R) models, both characterized by strong HMGB1-TLR4 driven pathology. The current study demonstrates a novel role for cathepsin V in TLR4 signaling and implicates cathepsin V as a novel target for first-generation HIV-PI compounds. The identification of cathepsin V as a target to block HMGB1-TLR4-driven inflammation could allow for a rapid transition of the discovery from the bench to the bedside. Disulfide HMGB1 drives pathologic inflammation in many models by activating signaling through TLR4. Cell-based screening identified the mammalian protease cathepsin V as a novel therapeutic target to inhibit TLR4-mediated inflammation induced by extracellular HMGB1 (disulfide form). We identified two protease inhibitors (PIs) that block cathepsin V and thereby inhibit disulfide HMGB1-induced TLR4 activation: saquinavir (SQV), a firstgeneration PI targeting viral HIV protease and STO33438 (334), targeting mammalian proteases. We discovered that cathepsin V binds TLR4 under basal and HMGB1-stimulated conditions, but dissociates in the presence of SQV over time. Thus cathepsin V is a novel target for first-generation HIV PIs and represents a potential therapeutic target of pathologic inflammation.

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