The polyamine analog diethylnorspermidine restricts Coxsackievirus B3 replication, but the virus acquires resistance via a non-catalytic site mutation in the 2A protease that decreases viral fitness.
Targeting polyamine catabolism with DENSpm restricts Coxsackievirus B3 replication in vitro, though the virus can develop resistance via 2A protease mutations at the cost of viral fitness.
Enteroviruses, including Coxsackievirus B3 (CVB3), are pervasive pathogens that cause significant disease, including cardiomyopathies. Unfortunately, no treatments or vaccines are available for infected individuals. We identified the host polyamine pathway as a potential drug target, as inhibiting polyamine biosynthesis significantly reduces enterovirus replication in vitro and in vivo. Here, we show that CVB3 is sensitive to polyamine depletion through the polyamine analog diethylnorspermidine (DENSpm), which enhances polyamine catabolism through induction of polyamine acetylation. We demonstrate that CVB3 acquires resistance to DENSpm via mutation of the 2A protease, which enhances proteolytic activity in the presence of DENSpm. Resistance to DENSpm occurred via mutation of a non-catalytic site mutation and results in decreased fitness. These data demonstrate that potential for targeting polyamine catabolism as an antiviral target as well as highlight a potential mechanism of resistance.
Hulsebosch et al. (Tue,) conducted a other in Coxsackievirus B3 infection. Diethylnorspermidine (DENSpm) was evaluated on Viral replication and resistance. The polyamine analog diethylnorspermidine restricts Coxsackievirus B3 replication, but the virus acquires resistance via a non-catalytic site mutation in the 2A protease that decreases viral fitness.