Abstract
ABSTRACTIn order to produce proteins essential for their propagation, many pathogenic human viruses, including SARS-CoV-2, the causative agent of COVID-19 respiratory disease, commandeer host biosynthetic machineries and mechanisms. Three major structural proteins, the spike, envelope and membrane proteins, are amongst several SARS-CoV-2 components synthesised at the endoplasmic reticulum (ER) of infected human cells prior to the assembly of new viral particles. Hence, the inhibition of membrane protein synthesis at the ER is an attractive strategy for reducing the pathogenicity of SARS-CoV-2 and other obligate viral pathogens. Using an in vitro system, we demonstrate that the small molecule inhibitor ipomoeassin F (Ipom-F) potently blocks the Sec61-mediated ER membrane translocation and/or insertion of three therapeutic protein targets for SARS-CoV-2 infection; the viral spike and ORF8 proteins together with angiotensin-converting enzyme 2, the host cell plasma membrane receptor. Our findings highlight the potential for using ER protein translocation inhibitors such as Ipom-F as host-targeting, broad-spectrum antiviral agents.This article has an associated First Person interview with the first author of the paper.
Highlights
Many viruses, including SARS-CoV-2 (Zhou et al, 2020; Zhu et al, 2020) (Fig. 1A), hijack the host cell secretory pathway to correctly synthesise, fold and assemble important viral proteins (Bojkova et al, 2020; Gordon et al, 2020; Sicari et al, 2020)
We show that the principle molecular basis for the ipomoeassin F (Ipom-F) sensitivity of SARS-CoV-2 proteins is their dependence on Sec61, as dictated by their individual structural features and membrane topologies (Fig. 3)
Ipom-F selectively inhibits endoplasmic reticulum (ER) translocation of the viral ORF8 and S proteins To explore the ability of Ipom-F to inhibit the ER translocation of a small, yet structurally diverse, panel of SARS-CoV-2 membrane and secretory-like proteins, we first used a wellestablished in vitro translation system supplemented with canine pancreatic microsomes (Fig. 2A)
Summary
Many viruses, including SARS-CoV-2 (Zhou et al, 2020; Zhu et al, 2020) (Fig. 1A), hijack the host cell secretory pathway to correctly synthesise, fold and assemble important viral proteins (Bojkova et al, 2020; Gordon et al, 2020; Sicari et al, 2020).
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