SARS-CoV-2 replication in the presence of lysosomotropic drugs

SARS-CoV-2 replication in the presence of lysosomotropic drugs refers to the study of viral entry and proliferation when the endosomal acidification pathway is pharmacologically disrupted. SARS-CoV-2 utilizes two primary entry routes: a surface-level pathway mediated by the protease TMPRSS2 and an endosomal pathway mediated by pH-dependent cathepsins (Hoffmann et al., 2020). Lysosomotropic agents, such as hydroxychloroquine, act as weak bases that partition into lysosomes and endosomes, raising the pH and thereby inactivating the proteases required for viral fusion (Liu et al., 2020). While these drugs show potent inhibition of viral replication in certain cell lines (like Vero cells) that lack TMPRSS2, they have largely failed in clinical settings for COVID-19 (Nirk et al., 2021). This failure is attributed to the virus's ability to bypass the endosomal route in human respiratory tissues by using the TMPRSS2-dependent pathway, which is unaffected by lysosomotropic agents (Shang et al., 2020).

Other names

Endosomal entry of SARS-CoV-2pH-dependent viral entryLysosomal pathway of SARS-CoV-2Cathepsin-mediated viral entry

Lysosomotropic drugs are weak bases that accumulate in acidic intracellular compartments like endosomes and lysosomes, increasing their internal pH. This neutralization inhibits the activity of pH-dependent acid hydrolases, such as Cathepsin L, which are necessary to cleave the SARS-CoV-2 spike protein and facilitate viral-endosomal membrane fusion (Liu et al., 2020; Hoffmann et al., 2020).