Niclosamide Is a Proton Carrier and Targets Acidic Endosomes with Broad Antiviral Effects
Human rhinoviruses (HRVs) are a major cause of the common cold. The more than one hundred serotypes, divided into species HRV-A and HRV-B, either bind intercellular adhesion molecule 1 (major group viruses) or members of the low-density lipoprotein receptor (minor group viruses) for cell entry. Some major group HRVs can also access the host cell via heparan sulphate proteoglycans. The cell attachment protein(s) of the recently discovered phylogenetic clade HRV-C is unknown. The respective receptors direct virus uptake via clathrin-dependent or independent endocytosis or via macropinocytosis. Triggered by ICAM-1 and/or the low pH environment in endosomes the virions undergo conformational alterations giving rise to hydrophobic subviral particles. These are handed over from the receptors to the endosomal membrane. According to the current view, the RNA genome is released through an opening at one of the fivefold axes of the icosahedral capsid and crosses the membrane through a pore presumably formed by viral proteins. Alternatively, the membrane may be ruptured allowing subviral particles and RNA to enter the cytosol. Whether a channel is formed or the membrane is disrupted most probably depends on the respective HRV receptor.