Therapeutic potential of Cidofovir (HPMPC, Vistide) for the treatment of DNA virus (i.e. herpes-, papova-, pox- and adenovirus) infections.
(S)-1-(3-Hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC, Cidofovir, Vistide) is an acyclic nucleoside phosphonate with broad-spectrum activity against a wide variety of DNA viruses including herpesviruses [Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus type 6 (HHV-6) and equine and bovine herpesviruses], papovaviruses [human polyoma virus and human papilloma virus (HPV)], adeno-, irido-, hepadna-, and poxviruses. HPMPC has proved effective against these viruses in different cell culture systems and/or animal models. The mechanism of action of HPMPC is based upon the interaction of its active intracellular metabolite, the diphosphorylated HPMPC derivative HPMPCpp, with the viral DNA polymerase. HPMPCpp has been shown to block CMV DNA synthesis by DNA chain termination following incorporation of two consecutive HPMPC molecules at the 3'-end of the DNA chain. HPMPC confers a prolonged antiviral action, which lasts for several days or weeks, thus allowing infrequent dosing (i.e. every week or every two weeks). This prolonged antiviral action is probably due to the very long intracellular half-life of the HPMPC metabolites, particularly the HPMPCp-choline adduct. In clinical studies, HPMPC has proved efficacious in the treatment of CMV retinitis, following both intravenous injection (3 or 5 mg/kg, every other week) and intravitreal injection (single dose of 20 micrograms per eye). Initial clinical trials also point to the efficacy of both systemic (intravenous) and topical HPMPC (1% ointment) in the treatment of acyclovir-resistant HSV infections, and of topical HPMPC (ointment or injection) in the treatment of pharyngeal, laryngeal and anogenital HPV infections. HPMPC is now being pursued in the topical and/or systemic (intravenous) treatment of various infections due to CMV, HSV, VZV, EBV, HPV, polyoma-, adeno- and poxviruses.
De Clercq
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Rega Institute for Medical Research, Katholieke Universiteit, Leuven.
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001483:Base Sequence; D002417:Cattle; D000077404:Cidofovir; D002986:Clinical Trials as Topic; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D004267:DNA Viruses; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008969:Molecular Sequence Data; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D017354:Point Mutation; D014777:Virus Diseases / Q000188:drug therapy* / Q000662:veterinary; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D003596:Cytosine; D004259:DNA-Directed DNA Polymerase; D000077404:Cidofovir