Inhibitors of signal peptide peptidase and subtilisin/kexin-isozyme 1 inhibit Ebola virus glycoprotein-driven cell entry by interfering with activity and cellular localization of endosomal cathepsins

Teresa Plegge, Martin Spiegel, Nadine Krüger, Inga Nehlmeier, Michael Winkler, Mariana González Hernández, Stefan Pöhlmann
  • PLoS ONE, April 2019, Public Library of Science (PLoS)
  • DOI: 10.1371/journal.pone.0214968

SPP and SKI-1 inhibitor block Ebola virus entry

What is it about?

Host cell proteases that activate viruses are potential targets for antiviral intervention. However, protease inhibitors are frequently not very specific and might thus interfere with virus infection in various ways. This study shows that inhibitors of the cellular proteases signal peptide peptidase (SPP) and subtilisin/kexin-isoenzyme 1 (SKI-1) inhibit Ebola virus glycoprotein (EBOV-GP)-mediated host cell entry, although no evidence for a role of these proteases in EBOV infection has previously been documented. Our results show that these inhibitors block entry indirectly by interfering with EBOV-GP priming by cathepsin B/L (CatB/L). Thus, we provide evidence that the SPP inhibitor blocks CatB/L activity and that the SKI-1 inhibitor interferes with localization of CatB/L in endosomes.

Why is it important?

Our study confirms that host cell proteases are a valid target for antiviral intervention but also highlight that protease inhibitors can block virus infection via indirect mechanisms. Moreover, our results demonstrate that the commercially available SPP inhibitor used for this study is not SPP specific but also blocks the enzymatic activity of CatB/L.

Perspectives

Professor Stefan Pöhlmann
German Primate Center

Further studies need to explore whether CatB/L are targets for antiviral intervention in the context of EBOV infection of non-human primates and humans.

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http://dx.doi.org/10.1371/journal.pone.0214968

The following have contributed to this page: Professor Stefan Pöhlmann