Human immunodeficiency virus (HIV) infection is often accompanied by infection with other pathogens, in particular herpes simplex virus type 2 (HSV-2). The resulting coinfection is involved in a vicious circle of mutual facilitations. Therefore, an important task is to develop a compound that is highly potent against both viruses to suppress their transmission and replication. Here, we report on the discovery of such a compound, designated PMEO-DAPym. We compared its properties with those of the structurally related and clinically used acyclic nucleoside phosphonates (ANPs) tenofovir and adefovir. We demonstrated the potent anti-HIV and -HSV activity of this drug in a diverse set of clinically relevant in vitro, ex vivo, and in vivo systems including (i) CD4⁺ T-lymphocyte (CEM) cell cultures, (ii) embryonic lung (HEL) cell cultures, (iii) organotypic epithelial raft cultures of primary human keratinocytes (PHKs), (iv) primary human monocyte/macrophage (M/M) cell cultures, (v) human ex vivo lymphoid tissue, and (vi) athymic nude mice. Upon conversion to its diphosphate metabolite, PMEO-DAPym markedly inhibits both HIV-1 reverse transcriptase (RT) and HSV DNA polymerase. However, in striking contrast to tenofovir and adefovir, it also acts as an efficient immunomodulator, inducing β-chemokines in PBMC cultures, in particular the CCR5 agonists MIP-1β, MIP-1α and RANTES but not the CXCR4 agonist SDF-1, without the need to be intracellularly metabolized. Such specific β-chemokine upregulation required new mRNA synthesis. The upregulation of β-chemokines was shown to be associated with a pronounced downmodulation of the HIV-1 coreceptor CCR5 which may result in prevention of HIV entry. PMEO-DAPym belongs conceptually to a new class of efficient multitargeted antivirals for concomitant dual-viral (HSV/HIV) infection therapy through inhibition of virus-specific pathways (i.e. the viral polymerases) and HIV transmission prevention through interference with host pathways (i.e. CCR5 receptor down regulation).
Balzarini, J., Andrei, G., Balestra, E., Huskens, D., Vanpouille, C., Introini, A., et al. (2013). A multi-targeted drug candidate with dual anti-HIV and anti-HSV activity. PLOS PATHOGENS, 9(7), e1003456-e1003456.
|Tipologia:||Articolo su rivista|
|Citazione:||Balzarini, J., Andrei, G., Balestra, E., Huskens, D., Vanpouille, C., Introini, A., et al. (2013). A multi-targeted drug candidate with dual anti-HIV and anti-HSV activity. PLOS PATHOGENS, 9(7), e1003456-e1003456.|
|Settore Scientifico Disciplinare:||Settore MED/07 - Microbiologia e Microbiologia Clinica|
|Revisione (peer review):||Sì, ma tipo non specificato|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1371/journal.ppat.1003456|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||2013|
|Titolo:||A multi-targeted drug candidate with dual anti-HIV and anti-HSV activity|
|Autori:||Balzarini, J; Andrei, G; Balestra, E; Huskens, D; Vanpouille, C; Introini, A; Zicari, S; Liekens, S; Snoeck, R; Holý, A; Perno, C; Margolis, L; Schols, D|
|Appare nelle tipologie:||01 - Articolo su rivista|
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