Proteolytic activation of the SARS-coronavirus spike protein: Cutting enzymes at the cutting edge of antiviral research

Abstract

The severe acute respiratory syndrome (SARS) pandemic revealed that zoonotic transmission of animal coronaviruses (CoV) to humans poses a significant threat to public health and warrants surveillance and the development of countermeasures. The activity of host cell proteases, which cleave and activate the SARS-CoV spike (S) protein, is essential for viral infectivity and constitutes a target for intervention. However, the identities of the proteases involved have been unclear. Pioneer studies identified cathepsins and type II transmembrane serine proteases as cellular activators of SARS-CoV and demonstrated that several emerging viruses might exploit these enzymes to promote their spread. Here, we will review the proteolytic systems hijacked by SARS-CoV for S protein activation, we will discuss their contribution to viral spread in the host and we will outline antiviral strategies targeting these enzymes. This paper forms part of a series of invited articles in Antiviral Research on “From SARS to MERS: 10 years of research on highly pathogenic human coronaviruses.”

TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections

“…It has been shown that SARS-CoV enters into cells via two distinct pathways: one is mediated by TMPRSS2 at the cell surface and the other done by cathepsin L/B in the endosome (Fig. 6) [43,44,50,51]. The serine protease inhibitor camostat can effectively protect mice infected with the otherwise lethal SARS-CoV from death, but treatment with both serine and cathepsin inhibitors failed to improve survival significantly over that achieved with camostat alone [52], indicating that SARS-CoV propagation and pathogenesis is mediated by TMPRSS2 rather than cathepsin in vivo.…”

MERS-CoV spike protein: Targets for vaccines and therapeutics

“…In addition to receptor recognition and binding, proteolysis between S1 and S2 is another critical determinant for CoV tropism and pathogenesis (Millet and Whittaker, 2015;Simmons et al, 2013). Similarly, MERS-S protein can be cleaved by different host proteases, which has previously been thoroughly reviewed .…”

Development of transgenic mouse model expressing porcine aminopeptidase N and its susceptibility to porcine epidemic diarrhea virus

“…However, these factors are probably present at insufficient levels in mice. Proteases are generally required for efficient viral entry and the CPEs of coronaviruses (Matsuyama et al, 2005;Simmons et al, 2004Simmons et al, , 2013. Although the viral receptors are usually expressed in various organs, the diseases caused by coronavirus infections are limited to the small intestines and/or lungs, which are enriched cellular proteases.…”