K777   Click here for help

GtoPdb Ligand ID: 11515

Synonyms: K-777 | K11777 | S-001 | SLV213
PDB Ligand
Compound class: Synthetic organic
Comment: K777 is a clinical stage irreversible cysteine protease inhibitor. It has reported activity at human cathepsin L and other CA clade cysteine proteases [2-5]. Original reports revealed anti-parasitic effects in vitro and in animal models [1-2,6].

SARS-CoV-2: Cathepsin L in human host cells is implicated in the processing (cleavage) of the viral spike protein of SARS coronaviruses, that is part of the viral entry process. K777 blocks SARS-CoV-2 infection in vitro.
Click here for help
2D Structure
Click here for help
Click here for structure editor
Physico-chemical Properties
Click here for help
Hydrogen bond acceptors 8
Hydrogen bond donors 2
Rotatable bonds 15
Topological polar surface area 107.2
Molecular weight 576.28
XLogP 4.17
No. Lipinski's rules broken 1
Click here for help
Canonical SMILES CN1CCN(CC1)C(=O)N[C@H](C(=O)N[C@H](CCS(=O)(=O)c1ccccc1)CCc1ccccc1)Cc1ccccc1
Isomeric SMILES CN1CCN(CC1)C(=O)N[C@H](C(=O)N[C@H](CCS(=O)(=O)c1ccccc1)CCc1ccccc1)Cc1ccccc1
InChI InChI=1S/C32H40N4O4S/c1-35-20-22-36(23-21-35)32(38)34-30(25-27-13-7-3-8-14-27)31(37)33-28(18-17-26-11-5-2-6-12-26)19-24-41(39,40)29-15-9-4-10-16-29/h2-16,28,30H,17-25H2,1H3,(H,33,37)(H,34,38)/t28-,30-/m0/s1
Bioactivity Comments
Evidence reported in 2015 showed that K777 blocked entry of pseudovirus forms of SARS-CoV and MERS-CoV into Vero E6 or HEK293 cells. This activity was attributed to its capacity to inhibit host cathepsin L. Subsequent to the pandemic spread of SARS-CoV-2, K777 was redeployed for this more recently evolved coronavirus. Studies showed that K777-mediated inhibition of human cathepsin L reduced SARS-CoV-2 infection of human and mouse cells without evident toxicity [3]. Cell types tested included Vero E6, HeLa/ACE2, Caco-2, and A549/ACE2 cells. K777 did not inhibit the two SARS-CoV-2 cysteine proteases, papain-like protease (PLpro) and 3CL-like/main protease (Mpro) in these studies.
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
cathepsin S Hs Inhibitor Inhibition 8.7 pKi - 3
pKi 8.7 (Ki 2x10-9 M) [3]
cathepsin L Hs Inhibitor Inhibition 7.3 pKi - 3
pKi 7.3 (Ki 5x10-8 M) [3]
cathepsin K Hs Inhibitor Inhibition 6.4 pKi - 3
pKi 6.4 (Ki 4x10-7 M) [3]
cathepsin B Hs Inhibitor Inhibition 5.5 pKi - 3
pKi 5.5 (Ki 3x10-6 M) [3]