Highlights d ZIKV preferentially infects glioblastoma stem cells (GSCs) rather than neural precursor cells d ZIKV kills SOX2 + cells from a diverse array of malignant brain tumors d SOX2 determines susceptibility to ZIKV infection with reduced antiviral responses d Integrin a v b 5 is a GSC marker and promotes Zika virus infection of GSCs
Host-cell cysteine proteases play an essential role in the processing of the viral
spike protein of SARS coronaviruses. K777, an irreversible, covalent inactivator of
cysteine proteases that has recently completed phase 1 clinical trials, reduced
SARS-CoV-2 viral infectivity in several host cells: Vero E6 (EC
50
< 74 nM),
HeLa/ACE2 (4 nM), Caco-2 (EC
90
= 4.3 μM), and A549/ACE2 (<80 nM).
Infectivity of Calu-3 cells depended on the cell line assayed. If Calu-3/2B4 was used,
EC
50
was 7 nM, but in the ATCC Calu-3 cell line without ACE2 enrichment,
EC
50
was >10 μM. There was no toxicity to any of the host cell
lines at 10–100 μM K777 concentration. Kinetic analysis confirmed that K777
was a potent inhibitor of human cathepsin L, whereas no inhibition of the SARS-CoV-2
cysteine proteases (papain-like and 3CL-like protease) was observed. Treatment of Vero
E6 cells with a propargyl derivative of K777 as an activity-based probe identified human
cathepsin B and cathepsin L as the intracellular targets of this molecule in both
infected and uninfected Vero E6 cells. However, cleavage of the SARS-CoV-2 spike protein
was only carried out by cathepsin L. This cleavage was blocked by K777 and occurred in
the S1 domain of the SARS-CoV-2 spike protein, a different site from that previously
observed for the SARS-CoV-1 spike protein. These data support the hypothesis that the
antiviral activity of K777 is mediated through inhibition of the activity of host
cathepsin L and subsequent loss of cathepsin L-mediated viral spike protein
processing.
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