MHV370 (MHV-370) is a potent, selective, orally bioavailable inhibitor of Toll-like receptors 7 and 8 (TLR7/8) with IC50 of 1.1 and 4.5 nM in cell-based assays.
MHV370 potently inhibited CL307- and R848-driven reporter gene activity in cells with IC50 of 15 nM and 7 nM, respectively.
MHV370 displayed no activity against other TLRs (TLR1/2, TLR2/6), tumor necrosis factor (TNF) receptor, and NOD1 at 10 uM.
MHV370 did not lead to cell toxicity at 10 uM, did not block ODN2216/TLR9-dependent IFN-α secretion from isolated human pDCs.
MHV370 potently suppressed production of multiple cytokines following activation of isolated monocytes with the TLR8-specific agonist TL8-0506, i.e., TNF, interleukin-6 (IL-6), and IL-1β.
MHV370 inhibited ssRNA-induced IFN-α and TNF responses on PBMCs with IC50 of 4.1 and 70 nM, respectively.
MHV370 is a potent, selective, and reversible antagonist of TLR7 and TLR8 in humans, and a selective TLR7 antagonist in mice.
MHV370 blocks activation of cell types that drive lupus, including B cells and pDCs.
MHV370 (5 mg, oral) suppresses acute TLR7-dependent immune activation in mice.
MHV370 suppresses ISGs in the TMPD peritonitis model, protects from lupus-like disease in the NZB/W F1 mouse model.