CGC-11047

The Zika virus (ZIKV) is primarily transmitted via an infected mosquito bite, during sexual intercourse, or in utero mother to child transmission. When a fetus is infected, both neurological malformations and deficits in brain development are frequently manifested. As such, there is a need for vaccines or drugs that may be used to cure ZIKV infections. Metabolic pathways play a crucial role in cell differentiation and development. More importantly, polyamines play a key role in replication and translation of several RNA viruses, including ZIKV, Dengue virus, and Chikungunya virus. Here, we present polyamine analogues (BENSpm and PG11047) and their corresponding polymer prodrug derivatives for inhibiting ZIKV infection by intersecting with polyamine catabolism pathways. We tested the compounds against ZIKV African (MR766) and Asian (PRVABC59) strains in human kidney epithelial (Vero) and glioblastoma derived (SNB-19) cell lines. Our results demonstrate potent inhibition of ZIKV viral replication in both cell lines tested. This antiviral effect was mediated by the upregulation of two polyamine catabolic enzymes, spermine oxidase, and spermidine (SMOX)/spermine N1-acetyltransferase (SAT1) as apparent reduction of the ZIKV infection following heterologous expression of SMOX and SAT1. On the basis of these observations, we infer potential use of these polyamine analogues to treat ZIKV infections.

The treatment of specific tumor cell lines with poly- and oligoamine analogs results in a superinduction of polyamine catabolism that is associated with cytotoxicity; however, other tumor cells show resistance to analog treatment. Recent data indicate that some of these analogs also have direct epigenetic effects. We, therefore, sought to determine the effects of combining specific analogs with an epigenetic targeting agent in phenotypically resistant human lung cancer cell lines. We show that the histone deacetylase inhibitor MS-275, when combined with (N1, N11)-bisethylnorspermine (BENSpm) or (N1, N12)-bis(ethyl)-cis-6,7-dehydrospermine tetrahydrochloride (PG-11047), synergistically induces the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase (SSAT), a major determinant of sensitivity to the antitumor analogs. Evidence indicates that the mechanism of this synergy includes reactivation of miR-200a, which targets and destabilizes kelch-like ECH-associated protein 1 (KEAP1) mRNA, resulting in the translocation and binding of nuclear factor (erythroid-derived 2)-like 2 (NRF2) to the polyamine-responsive element of the SSAT promoter. This transcriptional stimulation, combined with positive regulation of SSAT mRNA and protein by the analogs, results in decreased intracellular concentrations of natural polyamines and growth inhibition. The finding that an epigenetic targeting agent is capable of inducing a rate-limiting step in polyamine catabolism to overcome resistance to the antitumor analogs represents a completely novel chemotherapeutic approach. In addition, this is the first demonstration of miRNA-mediated regulation of the polyamine catabolic pathway. Furthermore, the individual agents used in this study have been investigated clinically; therefore, translation of these combinations into the clinical setting holds promise. Mol Cancer Ther; 12(10); 2088–99. ©2013 AACR.