title: New synthetic glutathione derivatives with increased antiviral activities.
abstract: A series of glutathione (GSH) derivatives with aliphatic chains of different lengths, coupled by peptides bound to the alpha-NH2 group of Glu, were synthesized. When added to several cell lines, the C6 (n-hexanoyl), C8 (n-octanoyl) and C12 (n-dodecanoyl) derivatives were toxic while the C2 (nethanoyl) and C4 (n-butanoyl) derivatives were not. Preliminary experiments were performed to investigate the potential antiviral activity of the C2 and C4 derivatives compared to GSH. The C4 derivative was the most potent and fully characterized. GSH-C4 is a poor substrate of GSH metabolizing enzymes; once oxidized by disulphide-bound formation, C4 is slowly reduced by GSH-reductase. GSH-C4 completely abrogated Sendai virus replication at 7.5 mM with an EC50 of 3.6 mM, compared to 7.5 mM for GSH. GSH-C4 completely inhibited herpes simplex virus (HSV-1) virus production in Vero cells at 10 mM, while the same dose of GSH caused only a 2.5 log10 reduction. Furthermore, the GSH-C4 treatment (7.5 mM) was able to markedly reduce the cytopathic effect of HSV-1 in Vero cells. Thus, GSH derivatives with increased hydrophobic properties are more effective antiviral agents against Sendai and HSV-1 viruses than GSH, suggesting their usefulness in antiviral therapy.
authors.affiliation: Institute of Microbiology, University of Rome La Sapienza, Rome, Italy.
authors.forename: Anna Teresa
authors.initials: AT
authors.lastname: Palamara
authors.forename: Giorgio
authors.initials: G
authors.lastname: Brandi
authors.forename: Luigia
authors.initials: L
authors.lastname: Rossi
authors.forename: Enrico
authors.initials: E
authors.lastname: Millo
authors.forename: Umberto
authors.initials: U
authors.lastname: Benatti
authors.forename: Lucia
authors.initials: L
authors.lastname: Nencioni
authors.forename: Alessandra
authors.initials: A
authors.lastname: Iuvara
authors.forename: Enrico
authors.initials: E
authors.lastname: Garaci
authors.forename: Mauro
authors.initials: M
authors.lastname: Magnani
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects; D005978:Glutathione / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D015394:Molecular Structure; D029082:Sendai virus / Q000187:drug effects / Q000502:physiology; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D005978:Glutathione