Enteroviruses (family of the Picornaviridae) cover a large group of medically important human pathogens for which no antiviral treatment is approved. Although these viruses have been extensively studied, some aspects of the viral life cycle, in particular morphogenesis, are yet poorly understood. We report the discovery of TP219 as a novel inhibitor of the replication of several enteroviruses, including coxsackievirus and poliovirus. We show that TP219 binds directly glutathione (GSH), thereby rapidly depleting intracellular GSH levels and that this interferes with virus morphogenesis without affecting viral RNA replication. The inhibitory effect on assembly was shown not to depend on an altered reducing environment. Using TP219, we show that GSH is an essential stabilizing cofactor during the transition of protomeric particles into pentameric particles. Sequential passaging of coxsackievirus B3 in the presence of low GSH-levels selected for GSH-independent mutants that harbored a surface-exposed methionine in VP1 at the interface between two protomers. In line with this observation, enteroviruses that already contained this surface-exposed methionine, such as EV71, did not rely on GSH for virus morphogenesis. Biochemical and microscopical analysis provided strong evidence for a direct interaction between GSH and wildtype VP1 and a role for this interaction in localizing assembly intermediates to replication sites. Consistently, the interaction between GSH and mutant VP1 was abolished resulting in a relocalization of the assembly intermediates to replication sites independent from GSH. This study thus reveals GSH as a novel stabilizing host factor essential for the production of infectious enterovirus progeny and provides new insights into the poorly understood process of morphogenesis.
Here we report on a novel class of enterovirus inhibitors that can be structurally described as 9-arylpurines. These compounds elicit activity against a variety of enteroviruses in the low microM range including Coxsackie virus A16, A21, A24, Coxsackie virus B3, and echovirus 9. Structure-activity relationship (SAR) studies indicate that a chlorine or bromine atom is required at position 6 of the purine ring for antiviral activity. The most selective compounds in this series inhibited Coxsackie virus B3 replication in a dose-dependent manner with EC(50) values around 5-8 microM. No toxicity on different cell lines was observed at concentrations up to 250 microM. Moreover, no cross-resistance to TBZE-029 and TTP-8307 CVB3 resistant strains was detected.
On the basis of the interesting inhibitory properties that lectins show against HIV-replication through their interaction with glycoprotein 120 (gp120), we here describe the design, synthesis, and anti-HIV evaluation of three series of 1,3,5-triazine derivatives (monomers, dimers, and trimers) functionalized with aromatic amino acids meant to mimic interactions that lectins establish with gp120. While monomers were inactive against HIV replication, dimers showed limited anti-HIV activity that is, however, considerably more significant in the trimers series, with EC(50) values in the lower μM range. These findings most likely reflect the requirement of multivalency of the 1,3,5-triazine derivatives to display anti-HIV activity, as lectins do. The pronounced anti-HIV activity (EC(50) ∼ 20 μM) is accompanied by the absence of toxicity in CEM T-cell line (CC(50) > 250 μM). Moreover, SPR experiments revealed that the prototype trimers with a central core of 2,4,6-triethylbenzene and six l-Trp or six l-Tyr residues at the periphery were efficient binders of CXCR4- and CCR5-tropic HIV-1 gp120 (estimated K(D): lower micromolar range). The collected data support the interest of this novel family of anti-HIV agents and qualify them as potential novel microbicide lead compounds.
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