K777 is a potent, orally active, and irreversible inhibitor of cysteine protease, functioning as a potent CYP3A4 inhibitor (IC50 = 60 nM) and a selective CCR4 antagonist, which inhibits chemotaxis. K777 irreversibly inhibits Cruzain, the major cysteine protease of Trypanosoma cruzi, and cathepsins B and L, targeting cathepsin-mediated cell entry and exhibiting broad-spectrum antiviral activity. It inhibits EBOV and SARS-CoV pseudovirus entry with IC50 values of 0.87 nM and 0.68 nM, respectively.

CYP3A4:60 nM (IC50)

K777 is a broad-spectrum antiviral and inhibits SARS-CoV, HCoV-229E, NL63, MERS-CoV, EBOV, SUDV, TAFV, RESTV, BEBOV, MARV and Nipah pseudovirus entry with IC50 values of 0.68 nM, 1.48 nM, 6.78 nM, 46.12 nM, 0.87 nM, 1.14 nM, 2.26 nM, 3.37 nM, 5.91 nM, 1.9 nM and 0.42 nM, respectively. K777 alone demonstrates up to 70% inhibition of 229E-S-mediated transduction in TMPRSS2 expressing cells. Simultaneous treatment with Camostat and K777 increases inhibition to ~ 90%[1]. K777 inhibits both CCL17 binding and CCL17-induced chemotaxis in Hut78 cells with IC50s of 57 and 8.9 nM, respectively. The K777-mediated inhibition of chemotaxis is potent even in the presence of a 10-fold higher concentration of CCL17. K777 induces CCR4 internalization with a 50% reduction of cell surface CCR4[3].

In C57BL/6 IFN-γR-KO mice, K777 ( 35-105 mg/kg; p.o.) rescues mice from otherwise lethal infections[4].