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, Brichacek, Beda, Scrimieri, Francesca, Schinazi, Raymond, Schols, Dominique, McGuigan, Christopher, Balzarini, Jan and Margolis, Leonid (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, 201 (4). pp. 635-643. ISSN 0022-1899

Full text not available from this repository.

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.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
Depositing User: Marco Derudas
Date Deposited: 22 Jul 2015 15:17
Last Modified: 22 Jul 2015 15:17
URI: http://sro.sussex.ac.uk/id/eprint/55687
📧 Request an update