Oral Treatment of Cowpox and Vaccinia Virus Infections in Mice with Ether Lipid Esters of Cidofovir

Abstract

Four newly synthesized ether lipid esters of cidofovir (CDV), hexadecyloxypropyl-CDV (HDP-CDV), octadecyloxyethyl-CDV (ODE-CDV), oleyloxypropyl-CDV (OLP-CDV), and oleyloxyethyl-CDV (OLE-CDV), were found to have enhanced activities against vaccinia virus (VV) and cowpox virus (CV) in vitro compared to those of CDV. The compounds were administered orally and were evaluated for their efficacies against lethal CV or VV infections in mice. HDP-CDV, ODE-CDV, and OLE-CDV were effective at preventing mortality from CV infection when treatments were initiated 24 h after viral inoculation, but only HDP-CDV and ODE-CDV maintained efficacy when treatments were initiated as late as 72 h postinfection. Oral pretreatment with HDP-CDV and ODE-CDV were also effective when they were given 5, 3, or 1 day prior to inoculation with CV, even when each compound was administered as a single dose. Both HDP-CDV and ODE-CDV were also effective against VV infections when they were administered orally 24 or 48 h after infection. In animals treated with HDP-CDV or ODE-CDV, the titers of both CV and VV in the liver, spleen, and kidney were reduced 3 to 7 log 10 . In contrast, virus replication in the lungs was not significantly reduced. These data indicate that HDP-CDV or ODE-CDV given orally is as effective as CDV given parenterally for the treatment of experimental CV and VV infections and suggest that these compounds may be useful for the treatment of orthopoxvirus infections in humans.Orthopoxvirus diseases continue to pose challenges to researchers preparing for a bioterrorist release of biological weapons of mass destruction. Rapid diagnostics for smallpox and the development of effective antiviral chemotherapies are two essential components for national preparedness (16,17). The in vitro and in vivo activities of cidofovir (CDV) against orthopoxviruses are well documented (3,4,8,9,15,18,(20)(21)(22)(23)(24); however, its usefulness is limited by the requirement for intravenous administration and dose-limiting nephrotoxicity (14). Orally active compounds with prolonged therapeutic levels in blood and reduced toxicity would be desirable for mass distribution in response to an actual release of the smallpox virus.Results from earlier studies with acyclovir and ganciclovir showed that alkoxyalkyl esters of the monophosphates of ganciclovir or acyclovir have improved oral bioavailabilities compared to those of the unmodified parent compounds and are effective against cytomegalovirus and herpes simplex virus infections (13). To improve the oral bioavailability of CDV, a novel series of analogs were synthesized by esterification with long-chain alkoxyalkanols. Hexadecyloxypropyl-CDV (HDP-CDV) and octadecyloxyethyl-CDV (ODE-CDV) were synthesized and evaluated in vitro for their efficacies against cowpox virus (CV) and vaccinia virus (VV) infections. As reported previously (15), HDP-CDV had 50% effective concentrations (EC 50 s) of 0.52 and 0.62 M against CV and VV, respectively, whereas the EC 50 s of CDV were 42 and 31 M, respectively. ODE-CD...

Differential pathogenesis of cowpox virus intranasal infections in mice induced by low and high inoculum volumes and effects of cidofovir treatment

“…Otherwise, the type of infection in mice resulting from the 50-μl i.n. challenge with the SF strain of cowpox virus is similar to the infection with the typical cowpox virus strain [1,5,6].…”

“…However, other investigators believe hepatitis is the cause of death. The rationale for this hypothesis is that although cidofovir protects mice from lethal cowpox virus infection, the surviving mice have only moderate decreases in lung virus titer, yet exhibit much more profound declines in liver virus titer [5,6]. A third proposed factor that may lead to death is the overproduction of inflammatory mediators (commonly referred to as a "cytokine storm") during such infections.…”

Hexadecyloxypropyl-cidofovir, CMX001, prevents adenovirus-induced mortality in a permissive, immunosuppressed animal model

“…Its bioavailability and cellular uptake are significantly enhanced because of the lipid moiety, which is cleaved inside the cell by phospholipase to liberate cidofovir. This increased cellular uptake of CMX001 results in enhanced activity compared with cidofovir against multiple double-strand DNA viruses, including poxvirus (22)(23)(24) and CMV (25,26) infections. Furthermore, the drug is 5-to 200-fold more potent in vitro than cidofovir against species A (Ad31), B (Ad3, Ad7), C (Ad5), and D (Ad8) Ads (27).…”

Inhibitory Activity of Alkoxyalkyl and Alkyl Esters of Cidofovir and Cyclic Cidofovir against Orthopoxvirus Replication In Vitro

“…Quenelle et al have reported that HDP-CDV and ODE-CDV were very effective in reducing mortality and viral TC-cCDV Ͼ100 Ͼ62 Ϯ 27 Ͼ100 Ϯ 0 replication in target organs of mice infected with CV and VV (11). These two compounds have been selected for preclinical pharmacokinetic, distribution, and toxicological studies.…”

“…HDP-CDV, ODE-CDV, and oleyloxypropyl-CDV (OLP-CDV) have oral bioavailabilities of 88 to 93% in mice (6) and have oral activity against vaccinia virus (VV) and cowpox virus (CV) infections in mice (11).…”