Characterization of Novel Piperidine-Based Inhibitor of Cathepsin B‑Dependent Bacterial Toxins and Viruses

Exploiting the host endocytic trafficking pathway is a common mechanism by which bacterial exotoxins gain entry to exert virulent effects upon the host cells. A previous study identified a small-molecule, 1-(2,6-dimethyl-1-piperidinyl)-3-[(2-isopropyl-5-methylcyclohexyl)­oxy]-2-propanol, that blocks the process of anthrax lethal toxin (LT) cytotoxicity. Here, we report the characterization of the bioactivity of this compound, which we named RC1. We found that RC1 protected host cells independently of LT concentration and also blocked intoxication by other bacterial exotoxins, suggesting that the target of the compound is a host factor. Using the anthrax LT intoxication pathway as a reference, we show that while anthrax toxin is able to bind to cells and establish an endosomal pore in the presence of the drug, the toxin is unable to translocate into the cytosol. We demonstrate that RC1 does not inhibit the toxin directly but rather reduces the enzymatic activity of host cathepsin B that mediates the escape of toxins into the cytoplasm from late endosomes. We demonstrate that the pathogenicity of Human cytomegalovirus and Herpes simplex virus 1, which relies on cathepsin B protease activity, is reduced by RC1. This study reveals the potential of RC1 as a broad-spectrum host-oriented therapy against several aggressive and deadly pathogens.