S-adenosyl methionine decarboxylase activity is required for the outcome of herpes simplex virus type 1 infection and represents a new potential therapeutic target.
All the available antiherpetic drugs are directed against viral proteins. Their extensive clinical use has led to the emergence of resistant viral strains. There is a need for the treatment of herpes infections due to resistant strains, especially for immunocompromised patients. To design new kinds of drugs, we have developed a strategy to identify cellular targets. Herpes simplex virus type 1 (HSV-1) infection is concomitant to a repression of most host protein synthesis. However, some cellular proteins continue to be efficiently synthesized. We speculated that some of them could determine the outcome of infection. Since two polyamines, spermidine and spermine, are components of the HSV-1 virions, we investigated whether enzymes involved in their synthesis could be required for viral infection. We show that inhibition of S-adenosyl methionine decarboxylase, a key enzyme of the polyamine metabolic pathway, prevents HSV-1 infection. Inhibition of polyamine synthesis prevents infection of culture cells with HSV-1 laboratory strains as well as clinical isolates that are resistant to the conventional antiviral drugs acyclovir and foscarnet. Our data provide the opportunity to develop molecules with a novel mechanism of action for the treatment of herpes infection.
Greco
Anna
A
INSERM U369, Faculté de Médecine Lyon-R.T.H. Laennec, Lyon, France. greco@cgmc.univ-lyon1.fr
Callé
Aleth
A
Morfin
Florence
F
Thouvenot
Danielle
D
Cayre
Myriam
M
Kindbeiter
Karine
K
Martin
Laetitia
L
Levillain
Olivier
O
Diaz
Jean-Jacques
JJ
D000212:Acyclovir / Q000494:pharmacology; D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors* / Q000235:genetics; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017245:Foscarnet / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006561:Herpes Simplex / Q000188:drug therapy* / Q000201:enzymology; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008935:Mitoguazone / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D013096:Spermine / Q000378:metabolism / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D013096:Spermine; D017245:Foscarnet; D012437:Adenosylmethionine Decarboxylase; D008935:Mitoguazone; D000212:Acyclovir