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Analysis of Resistance of Ebola Virus Glycoprotein-Driven Entry Against MDL28170, An Inhibitor of Cysteine Cathepsins

1
Infection Biology Unit, German Primate Center–Leibniz Institute for Primate Research, 37077 Göttingen, Germany
2
Faculty of Biology and Psychology, University Göttingen, 37073 Göttingen, Germany
*
Authors to whom correspondence should be addressed.
Pathogens 2019, 8(4), 192; https://doi.org/10.3390/pathogens8040192
Received: 27 August 2019 / Revised: 26 September 2019 / Accepted: 12 October 2019 / Published: 15 October 2019
Ebola virus (EBOV) infection can cause severe and frequently fatal disease in human patients. The EBOV glycoprotein (GP) mediates viral entry into host cells. For this, GP depends on priming by the pH-dependent endolysosomal cysteine proteases cathepsin B (CatB) and, to a lesser degree, cathepsin L (CatL), at least in most cell culture systems. However, there is limited information on whether and how EBOV-GP can acquire resistance to CatB/L inhibitors. Here, we addressed this question using replication-competent vesicular stomatitis virus bearing EBOV-GP. Five passages of this virus in the presence of the CatB/CatL inhibitor MDL28170 were sufficient to select resistant viral variants and sequencing revealed that all GP sequences contained a V37A mutation, which, in the context of native GP, is located in the base of the GP surface unit. In addition, some GP sequences harbored mutation S195R in the receptor-binding domain. Finally, mutational analysis demonstrated that V37A but not S195R conferred resistance against MDL28170 and other CatB/CatL inhibitors. Collectively, a single amino acid substitution in GP is sufficient to confer resistance against CatB/CatL inhibitors, suggesting that usage of CatB/CatL inhibitors for antiviral therapy may rapidly select for resistant viral variants. View Full-Text
Keywords: Ebola; cathepsin; glycoprotein Ebola; cathepsin; glycoprotein
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Hoffmann, M.; Kaufmann, S.V.; Fischer, C.; Maurer, W.; Moldenhauer, A.-S.; Pöhlmann, S. Analysis of Resistance of Ebola Virus Glycoprotein-Driven Entry Against MDL28170, An Inhibitor of Cysteine Cathepsins. Pathogens 2019, 8, 192.

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