A new class of dual-targeted antivirals: Monophosphorylated acyclovir prodrug derivatives suppress both human immunodeficiency virus type 1 and herpes simplex virus type 2

Christophe Vanpouille, Andrea Lisco, Marco Derudas, Elisa Saba, Jean-Charles B. Grivel, Beda Brichacek, Francesca Scrimieri, Raymond Schinazi, Dominique Schols, Christopher McGuigan, Jan Balzarini, Leonid Margolis

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Background. Human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 2 (HSV-2) are responsible for 2 intersecting epidemics in which the disease caused by 1 virus facilitates the transmission of and pathogenesis by the other. Therefore, suppression of one virus infection will affect the other. Acyclovir, a common antiherpetic drug, was shown to directly suppress both viruses in coinfected tissues. However, both antiviral activities of acyclovir are dependent on phosphorylation by the nucleoside kinase activity of coinfecting human herpesviruses. Methods. We developed acyclovir ProTides, monophosphorylated acyclovir with the phosphate group masked by lipophilic groups to allow efficient cellular uptake, and investigated their antiviral potential in cell lines and in human tissues ex vivo. Results. Acyclovir ProTides suppressed both HIV-1 and HSV-2 at median effective concentrations in the submicromolar range in ex vivo lymphoid and cervicovaginal human tissues and at 3-12 μmol/L in CD4+ T cells. Acyclovir ProTides retained activity against acyclovir-resistant HSV-2. Conclusions. Acyclovir ProTides represent a new class of antivirals that suppress both HIV-1 and HSV-2 by directly and independently blocking the key replicative enzymes of both viruses. Further optimization of such compounds may lead to double-targeted antivirals that can prevent viral transmission and treat the 2 synergistic diseases caused by HIV-1 and HSV-2. To our knowledge, the acyclovir ProTides described here represent the first example of acyclic nucleoside monophosphate prodrugs being active against HIV-1.

Original languageEnglish
Pages (from-to)635-643
Number of pages9
JournalJournal of Infectious Diseases
Volume201
Issue number4
DOIs
Publication statusPublished - 15 Feb 2010
Externally publishedYes

Fingerprint

Human Herpesvirus 2
Acyclovir
Prodrugs
Antiviral Agents
HIV-1
nucleoside phosphotransferase
Viruses
Herpesviridae
Virus Diseases
Nucleosides
Human Activities
Phosphates
Phosphorylation
T-Lymphocytes
Cell Line

ASJC Scopus subject areas

  • Infectious Diseases
  • Immunology and Allergy

Cite this

A new class of dual-targeted antivirals : Monophosphorylated acyclovir prodrug derivatives suppress both human immunodeficiency virus type 1 and herpes simplex virus type 2. / Vanpouille, Christophe; Lisco, Andrea; Derudas, Marco; Saba, Elisa; Grivel, Jean-Charles B.; Brichacek, Beda; Scrimieri, Francesca; Schinazi, Raymond; Schols, Dominique; McGuigan, Christopher; Balzarini, Jan; Margolis, Leonid.

In: Journal of Infectious Diseases, Vol. 201, No. 4, 15.02.2010, p. 635-643.

Research output: Contribution to journalArticle

Vanpouille, C, Lisco, A, Derudas, M, Saba, E, Grivel, J-CB, Brichacek, B, Scrimieri, F, Schinazi, R, Schols, D, McGuigan, C, Balzarini, J & Margolis, L 2010, 'A new class of dual-targeted antivirals: Monophosphorylated acyclovir prodrug derivatives suppress both human immunodeficiency virus type 1 and herpes simplex virus type 2', Journal of Infectious Diseases, vol. 201, no. 4, pp. 635-643. https://doi.org/10.1086/650343
Vanpouille, Christophe ; Lisco, Andrea ; Derudas, Marco ; Saba, Elisa ; Grivel, Jean-Charles B. ; Brichacek, Beda ; Scrimieri, Francesca ; Schinazi, Raymond ; Schols, Dominique ; McGuigan, Christopher ; Balzarini, Jan ; Margolis, Leonid. / A new class of dual-targeted antivirals : Monophosphorylated acyclovir prodrug derivatives suppress both human immunodeficiency virus type 1 and herpes simplex virus type 2. In: Journal of Infectious Diseases. 2010 ; Vol. 201, No. 4. pp. 635-643.
@article{000c5606238d4d8389aaf286bd4c2a96,
title = "A new class of dual-targeted antivirals: Monophosphorylated acyclovir prodrug derivatives suppress both human immunodeficiency virus type 1 and herpes simplex virus type 2",
abstract = "Background. Human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 2 (HSV-2) are responsible for 2 intersecting epidemics in which the disease caused by 1 virus facilitates the transmission of and pathogenesis by the other. Therefore, suppression of one virus infection will affect the other. Acyclovir, a common antiherpetic drug, was shown to directly suppress both viruses in coinfected tissues. However, both antiviral activities of acyclovir are dependent on phosphorylation by the nucleoside kinase activity of coinfecting human herpesviruses. Methods. We developed acyclovir ProTides, monophosphorylated acyclovir with the phosphate group masked by lipophilic groups to allow efficient cellular uptake, and investigated their antiviral potential in cell lines and in human tissues ex vivo. Results. Acyclovir ProTides suppressed both HIV-1 and HSV-2 at median effective concentrations in the submicromolar range in ex vivo lymphoid and cervicovaginal human tissues and at 3-12 μmol/L in CD4+ T cells. Acyclovir ProTides retained activity against acyclovir-resistant HSV-2. Conclusions. Acyclovir ProTides represent a new class of antivirals that suppress both HIV-1 and HSV-2 by directly and independently blocking the key replicative enzymes of both viruses. Further optimization of such compounds may lead to double-targeted antivirals that can prevent viral transmission and treat the 2 synergistic diseases caused by HIV-1 and HSV-2. To our knowledge, the acyclovir ProTides described here represent the first example of acyclic nucleoside monophosphate prodrugs being active against HIV-1.",
author = "Christophe Vanpouille and Andrea Lisco and Marco Derudas and Elisa Saba and Grivel, {Jean-Charles B.} and Beda Brichacek and Francesca Scrimieri and Raymond Schinazi and Dominique Schols and Christopher McGuigan and Jan Balzarini and Leonid Margolis",
year = "2010",
month = "2",
day = "15",
doi = "10.1086/650343",
language = "English",
volume = "201",
pages = "635--643",
journal = "Journal of Infectious Diseases",
issn = "0022-1899",
publisher = "Oxford University Press",
number = "4",

}

TY - JOUR

T1 - A new class of dual-targeted antivirals

T2 - Monophosphorylated acyclovir prodrug derivatives suppress both human immunodeficiency virus type 1 and herpes simplex virus type 2

AU - Vanpouille, Christophe

AU - Lisco, Andrea

AU - Derudas, Marco

AU - Saba, Elisa

AU - Grivel, Jean-Charles B.

AU - Brichacek, Beda

AU - Scrimieri, Francesca

AU - Schinazi, Raymond

AU - Schols, Dominique

AU - McGuigan, Christopher

AU - Balzarini, Jan

AU - Margolis, Leonid

PY - 2010/2/15

Y1 - 2010/2/15

N2 - Background. Human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 2 (HSV-2) are responsible for 2 intersecting epidemics in which the disease caused by 1 virus facilitates the transmission of and pathogenesis by the other. Therefore, suppression of one virus infection will affect the other. Acyclovir, a common antiherpetic drug, was shown to directly suppress both viruses in coinfected tissues. However, both antiviral activities of acyclovir are dependent on phosphorylation by the nucleoside kinase activity of coinfecting human herpesviruses. Methods. We developed acyclovir ProTides, monophosphorylated acyclovir with the phosphate group masked by lipophilic groups to allow efficient cellular uptake, and investigated their antiviral potential in cell lines and in human tissues ex vivo. Results. Acyclovir ProTides suppressed both HIV-1 and HSV-2 at median effective concentrations in the submicromolar range in ex vivo lymphoid and cervicovaginal human tissues and at 3-12 μmol/L in CD4+ T cells. Acyclovir ProTides retained activity against acyclovir-resistant HSV-2. Conclusions. Acyclovir ProTides represent a new class of antivirals that suppress both HIV-1 and HSV-2 by directly and independently blocking the key replicative enzymes of both viruses. Further optimization of such compounds may lead to double-targeted antivirals that can prevent viral transmission and treat the 2 synergistic diseases caused by HIV-1 and HSV-2. To our knowledge, the acyclovir ProTides described here represent the first example of acyclic nucleoside monophosphate prodrugs being active against HIV-1.

AB - Background. Human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 2 (HSV-2) are responsible for 2 intersecting epidemics in which the disease caused by 1 virus facilitates the transmission of and pathogenesis by the other. Therefore, suppression of one virus infection will affect the other. Acyclovir, a common antiherpetic drug, was shown to directly suppress both viruses in coinfected tissues. However, both antiviral activities of acyclovir are dependent on phosphorylation by the nucleoside kinase activity of coinfecting human herpesviruses. Methods. We developed acyclovir ProTides, monophosphorylated acyclovir with the phosphate group masked by lipophilic groups to allow efficient cellular uptake, and investigated their antiviral potential in cell lines and in human tissues ex vivo. Results. Acyclovir ProTides suppressed both HIV-1 and HSV-2 at median effective concentrations in the submicromolar range in ex vivo lymphoid and cervicovaginal human tissues and at 3-12 μmol/L in CD4+ T cells. Acyclovir ProTides retained activity against acyclovir-resistant HSV-2. Conclusions. Acyclovir ProTides represent a new class of antivirals that suppress both HIV-1 and HSV-2 by directly and independently blocking the key replicative enzymes of both viruses. Further optimization of such compounds may lead to double-targeted antivirals that can prevent viral transmission and treat the 2 synergistic diseases caused by HIV-1 and HSV-2. To our knowledge, the acyclovir ProTides described here represent the first example of acyclic nucleoside monophosphate prodrugs being active against HIV-1.

UR - http://www.scopus.com/inward/record.url?scp=75749153257&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=75749153257&partnerID=8YFLogxK

U2 - 10.1086/650343

DO - 10.1086/650343

M3 - Article

C2 - 20085496

AN - SCOPUS:75749153257

VL - 201

SP - 635

EP - 643

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

SN - 0022-1899

IS - 4

ER -