HIV protease inhibitor Saquinavir inhibits toll-like receptor 4 activation by targeting receptor dimerization

Abstract

ABSTRACTToll like receptor 4 (TLR4) is crucial in induction of innate immune response through recognition of invading pathogens or endogenous alarming molecules.Ligand-induced dimerization of TLR4 is required for the activation of downstream signaling pathways. TLR4 dimerization induces the activation of NF-kB and IRF3 through MyD88- or TRIF-dependent pathways. Saquinavir (SQV), a FDA-approved HIV protease inhibitor, has been shown to suppress the activation of NF-kB induced by HMGB1 by blocking TLR4-MyD88 association in proteasome-independent pathway. However, it remains nknown whether SQV is a HMGB1-specific and MyD88-dependent TLR4 signaling inhibitor and which precise signaling element of TLR4 is targeted by SQV. Our results showed that SQV inhibits both MyD88- and TRIF-dependent pathways in response to LPS, a critical sepsis inducer and TLR4 agonist, leading to downregulation of NF-kB and IRF3. SQV did not suppress MyD88-dependent pathway triggered by TLR1/2 agonist Pam3csk4. In the only TRIF-dependent pathway, SQV did not attenuate IRF3 activation induced by TLR3 agonist Poly(I:C). Furthermore, dimerization of TLR4 induced by LPS and HMGB1 was decreased by SQV. These results suggest that TLR4 receptor complex is the molecular target of SQV and shed light on that TLR4-mediated inmune responses and consequent risk for uncontrolled inflammation could be modulated by FDA-approved drug SQV.