Antiviral activity of cationic amphiphilic drugs

Abstract

Emerging and reemerging viral infections represent a major concern for human and veterinary public health and there is an urgent need for the development of broad-spectrum antivirals. Areas covered: A recent strategy in antiviral research is based on the identification of molecules targeting host functions required for infection of multiple viruses. A number of FDA-approved drugs used to treat several human diseases are cationic amphiphilic drugs (CADs) that have the ability to accumulate inside cells affecting several structures/functions hijacked by viruses during infection. In this review we summarized the CADs' chemical properties and effects on the cells and reported the main FDA-approved CADs that have been identified so far as potential antivirals in drug repurposing studies. Expert commentary: Although there have been concerns regarding the efficacy and the possible side effects of the off-label use of CADs as antivirals, they seem to represent a promising starting point for the development of broad-spectrum antiviral strategies. Further knowledge about their mechanism of action is required to improve their antiviral activity and to reduce the risk of side effects.

Keywords: Amiodarone; Crimean–Congo hemorrhagic fever virus; Herpes simplex virus; U18666A; Zika virus; antivirals; cationic amphiphilic drugs; chikungunya virus; chloroquine; dengue virus; ebola virus; emerging viruses; enterovirus; hepatitis C virus; ion channel blockers; protein kinase inhibitors; psychoactive drug; selective estrogen receptor modulators.

Figure 1.

Lysosomal trapping of cationic amphiphilic drugs (CADs). CADs are weak bases (B) and they cumulate in intracellular acidic compartments because the lysosomal membrane is much less permeable to the charged protonated bases (BH+) compared to the uncharged form. Accumulation of CADs inside the Late Endosomes/Lysosomes (LE/Lys) induces an enlargement of the organelles creating large vacuoles.