A Multi-targeted Drug Candidate with Dual Anti-HIV and Anti-HSV Activity

Jan Balzarini, Graciela Andrei, Emanuela Balestra, Dana Huskens, Christophe Vanpouille, Andrea Introini, Sonia Zicari, Sandra Liekens, Robert Snoeck, Antonín Holý, Carlo Federico Perno, Leonid Margolis, Dominique Schols

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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).

Original languageEnglish
Article numbere1003456
JournalPLoS Pathogens
Volume9
Issue number7
DOIs
Publication statusPublished - Jul 2013

Fingerprint

Tenofovir
HIV
Chemokines
Pharmaceutical Preparations
Cell Culture Techniques
Virus Diseases
Nude Mice
Up-Regulation
CCR5 Receptors
Viruses
Chemokine CCL5
Virus Internalization
Organophosphonates
Human Herpesvirus 2
Diphosphates
Immunologic Factors
Lymphoid Tissue
DNA-Directed DNA Polymerase
Coinfection
Keratinocytes

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Balzarini, J., Andrei, G., Balestra, E., Huskens, D., Vanpouille, C., Introini, A., ... Schols, D. (2013). A Multi-targeted Drug Candidate with Dual Anti-HIV and Anti-HSV Activity. PLoS Pathogens, 9(7), [e1003456]. https://doi.org/10.1371/journal.ppat.1003456

A Multi-targeted Drug Candidate with Dual Anti-HIV and Anti-HSV Activity. / Balzarini, Jan; Andrei, Graciela; Balestra, Emanuela; Huskens, Dana; Vanpouille, Christophe; Introini, Andrea; Zicari, Sonia; Liekens, Sandra; Snoeck, Robert; Holý, Antonín; Perno, Carlo Federico; Margolis, Leonid; Schols, Dominique.

In: PLoS Pathogens, Vol. 9, No. 7, e1003456, 07.2013.

Research output: Contribution to journalArticle

Balzarini, J, Andrei, G, Balestra, E, Huskens, D, Vanpouille, C, Introini, A, Zicari, S, Liekens, S, Snoeck, R, Holý, A, Perno, CF, Margolis, L & Schols, D 2013, 'A Multi-targeted Drug Candidate with Dual Anti-HIV and Anti-HSV Activity', PLoS Pathogens, vol. 9, no. 7, e1003456. https://doi.org/10.1371/journal.ppat.1003456
Balzarini J, Andrei G, Balestra E, Huskens D, Vanpouille C, Introini A et al. A Multi-targeted Drug Candidate with Dual Anti-HIV and Anti-HSV Activity. PLoS Pathogens. 2013 Jul;9(7). e1003456. https://doi.org/10.1371/journal.ppat.1003456
Balzarini, Jan ; Andrei, Graciela ; Balestra, Emanuela ; Huskens, Dana ; Vanpouille, Christophe ; Introini, Andrea ; Zicari, Sonia ; Liekens, Sandra ; Snoeck, Robert ; Holý, Antonín ; Perno, Carlo Federico ; Margolis, Leonid ; Schols, Dominique. / A Multi-targeted Drug Candidate with Dual Anti-HIV and Anti-HSV Activity. In: PLoS Pathogens. 2013 ; Vol. 9, No. 7.
@article{a867a83e1d5145b5955e36f40e03b04c,
title = "A Multi-targeted Drug Candidate with Dual Anti-HIV and Anti-HSV Activity",
abstract = "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).",
author = "Jan Balzarini and Graciela Andrei and Emanuela Balestra and Dana Huskens and Christophe Vanpouille and Andrea Introini and Sonia Zicari and Sandra Liekens and Robert Snoeck and Anton{\'i}n Hol{\'y} and Perno, {Carlo Federico} and Leonid Margolis and Dominique Schols",
year = "2013",
month = "7",
doi = "10.1371/journal.ppat.1003456",
language = "English",
volume = "9",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "7",

}

TY - JOUR

T1 - A Multi-targeted Drug Candidate with Dual Anti-HIV and Anti-HSV Activity

AU - Balzarini, Jan

AU - Andrei, Graciela

AU - Balestra, Emanuela

AU - Huskens, Dana

AU - Vanpouille, Christophe

AU - Introini, Andrea

AU - Zicari, Sonia

AU - Liekens, Sandra

AU - Snoeck, Robert

AU - Holý, Antonín

AU - Perno, Carlo Federico

AU - Margolis, Leonid

AU - Schols, Dominique

PY - 2013/7

Y1 - 2013/7

N2 - 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).

AB - 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).

UR - http://www.scopus.com/inward/record.url?scp=84884794379&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84884794379&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1003456

DO - 10.1371/journal.ppat.1003456

M3 - Article

VL - 9

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 7

M1 - e1003456

ER -