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. 2010 Dec;2(12):2803-30.
doi: 10.3390/v2122803. Epub 2010 Dec 22.

Cidofovir Activity against Poxvirus Infections

Graciela Andrei  1 , Robert Snoeck
Affiliations

Cidofovir Activity against Poxvirus Infections

Graciela Andrei et al. Viruses. 2010 Dec.

Abstract

Cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, HPMPC] is an acyclic nucleoside analog approved since 1996 for clinical use in the treatment of cytomegalovirus (CMV) retinitis in AIDS patients. Cidofovir (CDV) has broad-spectrum activity against DNA viruses, including herpes-, adeno-, polyoma-, papilloma- and poxviruses. Among poxviruses, cidofovir has shown in vitro activity against orthopox [vaccinia, variola (smallpox), cowpox, monkeypox, camelpox, ectromelia], molluscipox [molluscum contagiosum] and parapox [orf] viruses. The anti-poxvirus activity of cidofovir in vivo has been shown in different models of infection when the compound was administered either intraperitoneal, intranasal (aerosolized) or topically. In humans, cidofovir has been successfully used for the treatment of recalcitrant molluscum contagiosum virus and orf virus in immunocompromised patients. CDV remains a reference compound against poxviruses and holds potential for the therapy and short-term prophylaxis of not only orthopox- but also parapox- and molluscipoxvirus infections.

Keywords: acyclic nucleoside analog; cidofovir; poxviruses.

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Figures

Figure 1
Figure 1
Chemical structure of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC (CDV)) and its natural nucleotide.
Figure 2
Figure 2
Spectrum of anti-poxvirus activity of CDV and other acyclic nucleoside phosphonates (ANP)s. The antiviral properties of ANPs others than HPMPC (CDV) against variola virus, monkeypox virus and molluscum contagiosum virus has not been determined yet. ND: not determined.
Figure 3
Figure 3
Mechanism of action of Cidofovir (CDV). Once inside the cells, CDV needs to be activated by cellular enzymes. Pyrimidine nucleoside monophosphate (PNMP) kinase catalyses the conversion of CDV (CDV) to CDV-monophosphoryl (CDVp), which is then further phosphorylated to the active form, CDV-diphosphoryl (CDVpp) by nucleoside 5′-diphosphate (NDP) kinase. CDVp-choline is considered to serve as an intracellular reservoir for the mono- and diphosphoryl derivatives of CDV. The diphosphoryl derivative of CDV (i.e., CDVpp) interacts with the viral DNA polymerase as either competitive inhibitors [with respect to the natural substrates (i.e., dCTP)] or alternative substrates (thus leading to incorporation into DNA). CDV has a hydroxyl function in the acyclic side chain that would allow further chain elongation. For human cytomegalovirus (HCMV), chain termination occurs when two consecutive CDVpp are incorporated in the growing DNA chain. The mechanism of action of CDV and (S)-HPMPA against VACV DNA polymerase compared to CMV polymerase was adapted from [27].
Figure 4
Figure 4
Location of mutations in CDV-resistant E9L (DNA polymerase) mutants.
See this image and copyright information in PMC

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