Research Article: 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

Date Published: April 11, 2019

Publisher: Public Library of Science

Author(s): Teresa Plegge, Martin Spiegel, Nadine Krüger, Inga Nehlmeier, Michael Winkler, Mariana González Hernández, Stefan Pöhlmann, Jens H. Kuhn.


Emerging viruses such as severe fever and thrombocytopenia syndrome virus (SFTSV) and Ebola virus (EBOV) are responsible for significant morbidity and mortality. Host cell proteases that process the glycoproteins of these viruses are potential targets for antiviral intervention. The aspartyl protease signal peptide peptidase (SPP) has recently been shown to be required for processing of the glycoprotein precursor, Gn/Gc, of Bunyamwera virus and for viral infectivity. Here, we investigated whether SPP is also required for infectivity of particles bearing SFTSV-Gn/Gc. Entry driven by the EBOV glycoprotein (GP) and the Lassa virus glycoprotein (LASV-GPC) depends on the cysteine proteases cathepsin B and L (CatB/CatL) and the serine protease subtilisin/kexin-isozyme 1 (SKI-1), respectively, and was examined in parallel for control purposes. We found that inhibition of SPP and SKI-1 did not interfere with SFTSV Gn + Gc-driven entry but, unexpectedly, blocked entry mediated by EBOV-GP. The inhibition occurred at the stage of proteolytic activation and the SPP inhibitor was found to block CatL/CatB activity. In contrast, the SKI-1 inhibitor did not interfere with CatB/CatL activity but disrupted CatB localization in endo/lysosomes, the site of EBOV-GP processing. These results underline the potential of protease inhibitors for antiviral therapy but also show that previously characterized compounds might exert broader specificity than initially appreciated and might block viral entry via diverse mechanisms.

Partial Text

Anthropogenic drivers including climate change, exploitation of natural resources and global travel promote the constant emergence of novel pathogens in the human population [1–3]. Emerging viral infections can be associated with significant morbidity and mortality. For instance, the outbreak and subsequent spread of a new bunyavirus, severe fever with thrombocytopenia syndrome virus (SFTSV) in China in 2009, was associated with more than 7,000 cases until 2016 and a case-fatality rate of up to 30% [4, 5]. Moreover, SFTS cases have recently also been reported in other Asian countries, including South Korea [6] and Japan [7]. Similarly, the first outbreak of Ebola virus disease in West Africa in 2013 unfolded into a epidemic with more than 10,000 deaths and almost 30,000 cases [8]. At present, there are no approved antiviral drugs against SFTSV, EBOV and several other emerging viruses. The targeting of host cell factors required for spread of these viruses but dispensable for cellular survival is considered a promising approach to antiviral therapy, since the respective drugs might exert broad antiviral activity (in case several viruses depend on the same factor) and might be associated with a high barrier against resistance development.

Inhibition of host cell proteases responsible for processing of viral glycoproteins is an attractive approach to antiviral therapy. Such inhibitors might be particularly useful for treatment of emerging, highly pathogenic viruses against which no other antiviral options are available. Our results show that inhibitors of the host cell proteases SPP and SKI-1 do not impact SFTSV Gn + Gc-driven entry but block entry mediated by EBOV-GP. Moreover, we demonstrate that the SPP inhibitor blocks the enzymatic activity of the EBOV-GP processing host cell proteases CatB/CatL while the SKI-1 inhibitor interferes with localization of CatB in late endosomes/lysosomes, the site of EBOV-GP processing. Our results show that inhibition of SKI-1 blocks EBOV-GP-driven entry but also indicate that inhibitors of viral glycoprotein processing host cell proteases can interfere with viral entry in a direct and an indirect manner.




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