Antivaccinia activities of acyclic nucleoside phosphonate derivatives in epithelial cells and organotypic cultures.
Organotypic "raft" cultures of epithelial cells allow the reconstitution of a skin equivalent that is easily infectible with different viruses with cutaneous tropism. Among these, poxvirus and particularly vaccinia virus (VV) are good candidates for use in antiviral tests, giving histological pictures comparable to those observed in humans infected with smallpox. Therefore, we decided to evaluate a series of phosphonate derivatives for their ability to inhibit VV growth in epithelial cell monolayers, and the most powerful derivatives were tested in the organotypic cultures. The most active compound was 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine [(S)-HPMPA], followed by 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine, cyclic (S)-HPMPA, 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine [(S)-HPMPC; cidofovir, Vistide], and cyclic (S)-HPMPC. Cidofovir, which is on the market for the treatment of human cytomegalovirus retinitis in immunocompromised patients, is potentially a good candidate for the treatment of a poxvirus outbreak, in the absence of any vaccination.
Snoeck
R
R
Rega Institute for Medical Research, K.U. Leuven. Pathology Department, U.Z. Leuven, B-3000 Leuven, Belgium. robert.snoeck@rega.kuleuven.ac.be
Holý
A
A
Dewolf-Peeters
C
C
Van Den Oord
J
J
De Clercq
E
E
Andrei
G
G
D000225:Adenine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000821:virology*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000821:virology; D008962:Models, Theoretical; D008970:Molecular Weight; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology*; D009924:Organ Culture Techniques; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014615:Vaccinia / Q000188:drug therapy* / Q000821:virology; D014616:Vaccinia virus / Q000187:drug effects*
D000998:Antiviral Agents; D009705:Nucleosides; D063065:Organophosphonates; D009943:Organophosphorus Compounds; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D000225:Adenine