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 micromol/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.
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Vanpouille
authors.forename: Andrea
authors.initials: A
authors.lastname: Lisco
authors.forename: Marco
authors.initials: M
authors.lastname: Derudas
authors.forename: Elisa
authors.initials: E
authors.lastname: Saba
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Grivel
authors.forename: Beda
authors.initials: B
authors.lastname: Brichacek
authors.forename: Francesca
authors.initials: F
authors.lastname: Scrimieri
authors.forename: Raymond
authors.initials: R
authors.lastname: Schinazi
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.forename: Christopher
authors.initials: C
authors.lastname: McGuigan
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Leonid
authors.initials: L
authors.lastname: Margolis
mesh_terms: D000212:Acyclovir / Q000031:analogs & derivatives* / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002584:Cervix Uteri / Q000821:virology; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects*; D006558:Herpes Genitalis / Q000188:drug therapy; D018258:Herpesvirus 2, Human / Q000187:drug effects*; D006651:Histocytochemistry; D006801:Humans; D014066:Palatine Tonsil / Q000821:virology; D011355:Prodrugs / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; D000212:Acyclovir