K777

K777 is a cysteine protease inhibitor.¹ It inhibits human cathepsin S (K_i = 0.002 ?M) and human cathepsin L (K_i = 0.05 ?M), which cleaves the severe acute respiratory coronavirus 2 (SARS-CoV-2) spike glycoprotein, also known as the surface glycoprotein. K777 is selective for these proteases over human cathepsin K, -B, and -C (K_is = 0.4, 3, >100 ?M, respectively), as well as the SARS-CoV-2 cysteine proteases papain-like protease (PL^pro) and main protease (M^pro), also known as the 3C-like protease (3CL^pro; K_is = >100 ?M for both). It prevents cleavage of the spike protein S1 subunit in vitro and reduces the cytopathic effect of SARS-CoV-2 in infected Vero E6, HeLa/ACE2, and A549/ACE2 cells (EC₅₀s = <0.074, 0.004, and <0.080 ?M, respectively). K777 induces mortality in T. b. brucei trypanosomes (IC₅₀ = 0.1 ?M) and reduces myocardial damage in a canine model of T. cruzi infection when administered at a dose of 50 mg/kg twice per day.^2,3 It also inhibits chemokine (C-C motif) ligand 17 (CCL17) binding to, and CCL17-induced chemotaxis of, HuT 78 cells (IC₅₀s = 0.057 and 0.0089 ?M, respectively), as well as induces chemokine (C-C motif) receptor 4 (CCR4) internalization.⁴

1.Mellott, D.M., Tseng, C.-T., Drelich, A., et al.A clinical-stage cysteine protease inhibitor blocks SARS-CoV-2 infection of human and monkey cellsACS Chem. Biol.16(4)642-650(2021) 2.Troeberg, L., Morty, R.E., Pike, R.N., et al.Cysteine proteinase inhibitors kill cultured bloodstream forms of Trypanosoma brucei bruceiExp. Parasitol.91(4)349-355(1999) 3.Barr, S.C., Warner, K.L., Kornreic, B.G., et al.A cysteine protease inhibitor protects dogs from cardiac damage during infection by Trypanosoma cruziAntimicrob. Agents Chemother.49(12)5160-5161(2005) 4.Sato, T., Iwase, M., Miyama, M., et al.Internalization of CCR4 and inhibition of chemotaxis by K777, a potent and selective CCR4 antagonistPharmacology91(5-6)305-313(2013)