endocytic vesicle lumen
Lysosomes play critical roles in human biology receiving, trafficking, processing, and degrading biological molecules from cellular processes such as endocytosis, phagocytosis, autophagy and secretion. Lysosomes house around sixty proteolytic enzymes, among them cathepsins. Cathepsins are involved in many processes involving cell death, protein degradation, post-translational modifications of proteins, extracellular matrix (ECM) remodeling, autophagy, and immune signaling. The early stages of the viral life cycle involve the cleavage of the viral spike protein by cathepsin L (CTSL) in late endosomes, facilitating viral RNA release to continue viral replication. Teicoplanin, a glycopeptide antibiotic used to treat Gram-positive bacterial infection, especially in Staphylococcal infections, was shown to have efficacy in vitro against Ebola Virus, MERS and SARS-CoV-1 (Zhou et al. 2016).
Teicoplanin is thought to inhibit the low pH cleavage of the viral spike protein by CTSL in late endosomes thereby preventing the release of genomic viral RNA and the continuation of virus replication cycle (Baron et al. 2020). The target sequence that serve as the cleavage site for CTSL is conserved in the SARS-CoV-2 spike protein (Zhou et al. 2020 [preprint]). Further investigation is required to determine the therapeutic potential of teicoplanin in COVID-19 patients.
Relacatib is an investigational drug trialed for the treatment of osteoporosis (Duong et al. 2016). It is a potent CTSK inhibitor but also shows activity against CTSL (Kumar et al. 2007) so could potentially be investigated for Covid-19 patients. The antileprotic drug clofazimine and the antituberculous drugs rifampicin and isoniazid have been shown to inhibit cathepsins B, H and L from purified goat and bovine brains (Kamboj et al. 2003).