184.108.40.206 Cidofovir (HPMPC). To promptly identify an anti-poxvirus drug that could be immediately available in the event of a bioter-rorism attack, initial attention has focused on currently approved antiviral agents. Recent preclinical studies against vaccinia and cow-pox viruses have identified cidofovir (CDV) as a promising candidate. Cidofovir was first described in the literature in 1987 by De Clercq and Holy (467) and was approved in 1996 by the U.S. FDA as an intravenous treatment for human cytomegalovirus (HCMV) retinitis in AIDS patients under the licensed name Vistide (468-470). Once inside the cells, cidofovir follows two-step phosphorylation by cellular enzymes first to cidofovir monophosphate, CDVp, (e.g., by pyrimidine nucleoside monophosphate kinase) then to cidofovir diphosphate, CDVpp (e.g., by pyruvate kinase) (471). The latter, structurally analogous to a nucleoside triphosphate, serves as a competitive inhibitor of dCTP and an alternative substrate for HCMV DNA polymerase (472,473). Incorporation of a single cidofovir molecule causes a 31% decrease of in the rate of DNA elongation by HCMV DNA polymerase; incorporation of two consecutive molecules prohibits the DNA from further elongation (474). Furthermore, the intracellular cidofovir metabolites, namely CDVp, CDVpp, and CDVp choline, have very long half-life and these molecules confer a long-lasting antiviral response of cidofovir and infrequent dosing for antiviral therapy (469,475,476).
Cidofovir has broad-spectrum activity against various DNA virus, including poly-omaviruses, papillomaviruses, adenoviruses, herpesviruses, and poxviruses (468, 469, 475, 476).Huggins et al. reported that, in Vero and BSC-40 cells, cidofovir inhibited vaccinia, cow-pox, camelpox, and monkeypox viruses with EC,, values in the range of 30-90 fjM and variola virus in the range of 10 yM (Table 10.4) (477). It seemed that variola virus was most sensitive to cidofovir than the other or-thopoxviruses in this particular study.
Several different animal models have been used to assess the therapeutic potential of cidofovir for the treatment of poxvirus infections. In earlier studies, De Clercq et al. had used intravenous injection of vaccinia virus to infect the mice and measured the suppression of tail lesion formation to assess a compound's antiviral effect (465). Similarly infected SCID mice also die from the disseminate vaccinia infection in addition to the development of tail lesions. In such infected SCID mice, cidofovir was shown to significantly delay the mean day of death using either treatment or prophylactic regimen (478). However, inoculation of virus by injection does not simulate the respiratory exposure that occurs in natural smallpox infection nor in a bioterrorist scenario, namely infection acquired by aerosol route. To mimic the natural infection, Bray et al. (479) and Smee et al. (480-482) demonstrated that aerosol or intranasal infection of BALB/c mice with vaccinia virus or cowpox virus caused the infected animal to develop pneumonia, lose weight, and eventually die from the disease. The efficacy of cidofovir observed in these new models can be summarized by the following.
Cidofovir was active by intraperitoneal and intranasal routes against wild-type virus infections at non-toxic doses. It was not effective against infections caused by the cidofo-vir-resistant cowpox virus, and is not active orally.
• The efficacy of cidofovir against wild-type cowpox virus infections was similar to its activity against vaccinia virus infections.
• Mice could benefit from as little as a single treatment given a few days before or up to 4 days after virus exposure.
• Daily dosing with cidofovir was more beneficial than the single treatment regimen.
In a meeting presentation, Huggins reported that cynomolgus monkeys infected with monkeypox by small particle aerosol inoculation developed classical poxvirus lesions and pulmonary distress and that treatment of cidofovir, initiated on the day of infection, completely protected the animals from clinical and laboratory signs of disease (483). Topical cidofovir has been used to treat molluscum contagiosum (poxvirus) infections in AIDS patients (484).
In a bioterrorist attack, the number of exposed individuals is expected to be large; therefore, it may be technically difficult to administer cidofovir by injection. Because oral bioavailability of cidofovir is less than 5%,ad-ministration with an orally active prodrug form of cidofovir would be an ideal alternative under such circumstance.
Several reports by Hostetler et al. have shown that the oral bioavailability of nucleo-sides could be improved by conjugation with certain ether lipid groups, presumably by increasing oral absorption and cell membrane penetration (seereferences in Ref. 485). Cidofovir derivatives, HDP-CDV (196) and ODE-CDV (197), obtained by esterification of cido-
fovir with two long-chain alkoxyalkanols (3-hexadecyloxy-l-propanol and 3-octadecyloxy-1-ethanol, respectively) significantly enhanced both antiviral potency and selective indexes
fovir with two long-chain alkoxyalkanols (3-hexadecyloxy-l-propanol and 3-octadecyloxy-1-ethanol, respectively) significantly enhanced both antiviral potency and selective indexes w
Table 10.4 In Vitro Activity of Cidofovir, Ribavirin, Methisazone, Carbocyclic 3-Deazaadenosine,and 3-Deazaneplanocin A Against Vaccinia, Cowpox, Camelpox, Monkeypox, and Variola Viruses (477)
EC50 (jllM) in Indicated Cell Line
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