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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 contribution
posted on 2023-06-08, 21:50 authored by Christophe Vanpouille, Andrea Lisco, Marco Derudas, Elisa Saba, Jean-Charles Grivel, Beda Brichacek, Francesca Scrimieri, Raymond Schinazi, Dominique Schols, Christopher McGuigan, Jan Balzarini, Leonid Margolis
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.

History

Publication status

  • Published

Journal

Journal of Infectious Diseases

ISSN

0022-1899

Publisher

Oxford University Press

Issue

4

Volume

201

Page range

635-643

Department affiliated with

  • Chemistry Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2015-07-22

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