Here we report that our lead anti-retroviral (ARV) drug candidate Stampidine [2,â��3â��-didehydro-3â��-deoxythymidine- 5â��-(p-bromophenyl methoxy alaninyl phosphate)] results in methylation of a network of HIV-responsive regulatory genes in T-cells, including several genes for HIV-dependency factors (HDFs). Stampidine epigenetically modulates the host transcriptome in a unique manner, silences expression of a distinct set of genes encoding transcription factors and signal transduction molecules, and prevents HIV infection from distorting and disrupting key cellular transcriptional networks. At nanomolar concentrations that are 4-logs lower than those achieved at its non-toxic dose levels in mice, rats, cats, and dogs, Stampidine switched off genes for several HDFs that are required for HIV replication in T-cells. Notably, Stampidine reversed the effects of HIV exposure on the host transcriptome regardless of NRTI-sensitivity or RT mutations of the HIV isolate used and inhibited the replication of 17 NRTI-resistant HIV- 1 strains, including recombinant HIV clones containing common patterns of RT mutations responsible for NRTI resistance, in human peripheral blood mononuclear cells (PBMC) with subnanomolar-nanomolar IC50 values (Mean �± SEM = 12.0 �± 3 .2 nM). Unlike available ARV agents that disrupt a specific step in the life-cycle of HIV, Stampidine has the potential to abrogate all steps in the life cycle of HIV.
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