Knowing that Z-Tyr-Ala-CHN2 is a cathepsin L inhibitor also helps explain why the compound has broad-spectrum activity as, in addition to the S protein of SARS-CoV-1 and SARS-CoV-2, the HCoV-299E S protein can also be activated by TMPRSS2 and cathepsin L. Thus, in cell types where TMPRSS2 expression is minimal or lacking, like HeLa-hACE2, cathepsin L inhibition is expected to prevent infection of HCoV-229E. This evidence concerns the gene TMPRSS2 and infection.