Inhibition of HIV-1 gene expression by Ciclopirox and Deferiprone, drugs that prevent hypusination of eukaryotic initiation factor 5A

Abstract

At clinically relevant concentrations, two widely used drugs blocked HIV-1 replication ex vivo. They specifically inhibited expression from the HIV-1 promoter at the level of transcription initiation. Both drugs interfered with the hydroxylation step in the hypusine modification of eIF5A. These results have profound implications for the potential therapeutic use of these drugs as antiretrovirals and for the development of optimized analogs.

Phenyl-1-Pyridin-2yl-Ethanone-Based Iron Chelators Increase IκB-α Expression, Modulate CDK2 and CDK9 Activities, and Inhibit HIV-1 Transcription

“…Export of unspliced HIV-1 mRNA requires the HIV-1 Rev protein and host elongation factor 5A (eIF5␣), which contains N-epsilon-4-amino-2-hydroxybutyl-lysine (hypusine), produced by deoxyhypusine hydroxylase (DOHH), an iron-containing enzyme (54). The topical fungicide ciclopirox and the iron chelator deferiprone were shown to inhibit HIV-1 gene expression by interfering with the hydroxylation step in the hypusine modification of eIF5␣ (55). More recently, ciclopirox and deferiprone were shown to induce apoptosis though mitochondrial membrane depolarization in HIV-infected T cells, thus promoting selective elimination of HIV-1-infected cells in long-term culture (56).…”

Iron Chelators of the Di-2-pyridylketone Thiosemicarbazone and 2-Benzoylpyridine Thiosemicarbazone Series Inhibit HIV-1 Transcription: Identification of Novel Cellular Targets—Iron, Cyclin-Dependent Kinase (CDK) 2, and CDK9

“…The eIF5␣ protein contains N--4-amino-2-hydroxybutyl-lysine (hypusine) that is produced by deoxyhypusine hydroxylase, an iron-containing enzyme (Kim et al, 2006). The topical fungicide ciclopirox (which also is an iron chelator) and the orally active chelator deferiprone inhibit HIV-1 gene expression interfering with the hydroxylation step in the hypusine modification of eIF5␣ (Hoque et al, 2009). Furthermore, assembly of the HIV capsid requires an ATP-binding protein, ABCE1, which contains iron-sulfur clusters (Barthelme et al, 2007) and binds to HIV-1 Gag protein (Zimmerman et al, 2002).…”

The spermidine analogue GC7 (N1-guanyl-1,7-diamineoheptane) induces autophagy through a mechanism not involving the hypusination of eIF5A

“…For example, in hepatocellular carcinoma, over-expression of eIF5A2 was reported to be associated with tumour features that indicate poor prognosis, such as the presence of tumour metastasis and venous infiltration (Lee et al 2010). Furthermore, the clinical drugs ciclopirox and deferiprone, by inhibiting eIF5A hypusination, impair the transcription of the HIV-1 promoters and decrease HIV-1 gene expression (Hoque et al 2009). Based on the considerable therapeutic interest in eIF5A as a selective target for drug development through inhibition of hypusination, the GC7 off-target effect described in this study acquires particular relevance and should be taken into full consideration for the use of GC7 in clinical trials.…”