title: In vitro evaluation of the anti-orf virus activity of alkoxyalkyl esters of CDV, cCDV and (S)-HPMPA.
abstract: Acyclic nucleoside phosphonates (ANPs) and in particular (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC, cidofovir, CDV, Vistide) and its adenine counterpart (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine [(S)-HPMPA] are highly active against orf virus infections. This parapoxvirus commonly causes infection in sheep, goats, but also humans. Alkoxyalkyl esters of CDV have an increased oral bioavailability and are more active against orthopoxviruses than the parent compounds. In the present study, the potency of several alkoxyalkyl esters of CDV, cyclic cidofovir (cCDV) and (S)-HPMPA was evaluated against different orf virus isolates in two cell types, human embryonic lung (HEL) fibroblast and primary lamb keratinocytes. Each prodrug was at least 10-fold more active than its parent compound in both cell types. Of all the compounds tested, the (S)-HPMPA alkoxyalkyl esters showed the highest activity and selectivity against orf virus. Our results support the development of alkoxyalkyl esters of ANPs as antivirals not only for the treatment of complicated human orf lesions, but also in the therapy and prophylaxis of contagious ecthyma in sheep and goats.
authors.affiliation: Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Dal Pozzo
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.forename: Ilya
authors.initials: I
authors.lastname: Lebeau
authors.forename: James R
authors.initials: JR
authors.lastname: Beadle
authors.forename: Karl Y
authors.initials: KY
authors.lastname: Hostetler
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D000998:Antiviral Agents / Q000633:toxicity*; D002460:Cell Line; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D004474:Ecthyma, Contagious / Q000188:drug therapy*; D005347:Fibroblasts / Q000187:drug effects / Q000821:virology; D006801:Humans; D066298:In Vitro Techniques; D015603:Keratinocytes / Q000187:drug effects / Q000821:virology; D008168:Lung / Q000166:cytology; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology; D009923:Orf virus / Q000187:drug effects*; D063065:Organophosphonates / Q000737:chemistry / Q000633:toxicity*; D011355:Prodrugs / Q000494:pharmacology; D012680:Sensitivity and Specificity; D012756:Sheep
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides; D063065:Organophosphonates; D011355:Prodrugs; D003596:Cytosine; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D000225:Adenine; D000077404:Cidofovir