Glycopeptide Antibiotic Teicoplanin Inhibits Cell Entry of SARS-CoV-2 by Suppressing the Proteolytic Activity of Cathepsin L

Abstract

Since the outbreak of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), public health worldwide has been greatly threatened. The development of an effective treatment for this infection is crucial and urgent but is hampered by the incomplete understanding of the viral infection mechanisms and the lack of specific antiviral agents. We previously reported that teicoplanin, a glycopeptide antibiotic that has been commonly used in the clinic to treat bacterial infection, significantly restrained the cell entry of Ebola virus, SARS-CoV, and MERS-CoV by specifically inhibiting the activity of cathepsin L (CTSL). Here, we found that the cleavage sites of CTSL on the spike proteins of SARS-CoV-2 were highly conserved among all the variants. The treatment with teicoplanin suppressed the proteolytic activity of CTSL on spike and prevented the cellular infection of different pseudotyped SARS-CoV-2 viruses. Teicoplanin potently prevented the entry of SARS-CoV-2 into the cellular cytoplasm with an IC50 of 2.038 μM for the Wuhan-Hu-1 reference strain and an IC50 of 2.116 μM for the SARS-CoV-2 (D614G) variant. The pre-treatment of teicoplanin also prevented SARS-CoV-2 infection in hACE2 mice. In summary, our data reveal that CTSL is required for both SARS-CoV-2 and SARS-CoV infection and demonstrate the therapeutic potential of teicoplanin for universal anti-CoVs intervention.

Development and evaluation of a novel chromium III-based compound for potential inhibition of emerging SARS-CoV-2 variants

“…SARS-CoV-2 enters host cells via endosomes, and pH and cathepsins are key factors determining viral entry through the endosomal pathway. Teicoplanin, a cathepsin inhibitor, directly prevents viral genome entry into the cytoplasm [ 28 ]. Additionally, compounds such as azithromycin, chloroquine, and hydroxychloroquine indirectly inhibit viral genome entry by altering pH levels and suppressing cathepsin activity [ 26 , 27 ].…”

Development of SARS-CoV-2 entry antivirals

“…Teicoplanin, a commonly-used clinical glycopeptide antibiotic, significantly inhibited the viral entry of Ebola virus, SARS-CoV, and MERS-CoV by inhibiting the activity of cathepsin L ( Table 4 ) (N. Zhou, Pan, Zhang, Li, Zhang, Bai, et al., 2016 ). Interestingly, teicoplanin could also inhibit the entry of SARS-CoV-2 in HEK293T-hACE2 high cells at a relatively low and safe dose, by suppressing the proteolytic activity of cathepsin L (F. Yu, Pan, Huang, Ying, Liu, Fan, et al., 2022 ). A recent study found that Omicsynin B4 is a potent inhibitor of both cathepsin L and TMPRSS2 at sub-nanomolar or sub-micromolar levels, respectively.…”

Cathepsins and SARS‐CoV‐2 infection: From pathogenic factors to potential therapeutic targets

“…Dalbavancin (a teicoplanin homologue) can inhibit CatL as well as the entry of SARS‐CoV‐2. The IC 50 of teicoplanin against different variants of SARS‐CoV‐2 in vitro is <5 μM (Yu et al, 2022).…”