Abstract
Here we report that our lead anti-retroviral (ARV) drug candidate Stampidine (2,'3'-didehydro-3'-deoxythymidine- 5'-(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 IC 50 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.
Highlights
Human Immunodeficiency Virus type 1 (HIV-1) infection remains a global health concern affecting millions of individuals worldwide [13]
Pre-exposure prophylaxis (PrEP), an evolving new approach to HIV prevention in which ARV agents are used prior to potential HIV exposure in an attempt to reduce the likelihood of HIV infection post exposure in the context of unprotected heterosexual intercourse [8,9,10], has encountered difficulties in part due to ARV drug resistance [11,12,13]
There is an urgent need for potent antiHIV agents that are active against ARV drug-resistant HIV strains
Summary
Human Immunodeficiency Virus type 1 (HIV-1) infection remains a global health concern affecting millions of individuals worldwide [13]. Antiretroviral (ARV) treatment regimens employing combinations of drugs from at least two of the three classes of ARV therapy, namely Nucleoside Analogue RT Inhibitors (NRTI), Non-Nucleoside Analogue RT Inhibitors (NNRTI), and protease inhibitors, exhibit a potent and sustained antiviral effect and confer consistent long-term viral suppression in patients with HIV infection [1,2,3]. Each of these drugs can select for drug-resistant HIV strains and the emergence of ARV drug resistance limits their clinical benefit [4,5,6,7]. 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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