A Novel Peptide Aldehyde with Activity against Human Cytomegalovirus in Two Different<i>in Vivo</i>Models

Weber, Olaf; Reefschläger, J; Rübsamen‐Waigmann, Helga; Raddatz, Siegfried; Hesseling, Matthias; Häbich, Dieter

doi:10.1177/095632020001100105

Cited by 8 publications

(4 citation statements)

References 20 publications

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“…There have been a number of models used in which immunocompromised mice have been implanted with CMV-infected cells (2,31) or human tissue implants that could subsequently be infected with HCMV (5,7,23,42). With the models in which human fetal tissue is implanted either into the eye or under the kidney capsule of SCID mice, the implants infected with HCMV and animals treated with experimental compounds have been particularly useful and appear to be predictive of the outcome in humans (23).…”

Section: Discussionmentioning

confidence: 99%

Oral Treatment of Murine Cytomegalovirus Infections with Ether Lipid Esters of Cidofovir

Kern

Collins

Wan

et al. 2004

Antimicrob Agents Chemother

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To improve the oral bioavailability of cidofovir (CDV), a series of ether lipid ester prodrugs were synthesized and evaluated for activity against murine cytomegalovirus (MCMV) infection. Four of these analogs, hexadecyloxypropyl (HDP)-CDV, octadecyloxyethyl (ODE)-CDV, oleyloxyethyl (OLE)-CDV, and oleyloxypropyl (OLP)-CDV, were found to have greater activity than CDV against human CMV and MCMV in vitro. The efficacy of oral treatment with these compounds against MCMV infections in BALB/c mice was then determined. Treatment with HDP-CDV, ODE-CDV, OLE-CDV, or OLP-CDV at 2.0 to 6.7 mg/kg of body weight provided significant protection when daily treatments were initiated 24 to 48 h after viral inoculation. Additionally, HDP-CDV or ODE-CDV administered twice weekly or as a single dose of 1.25 to 10 mg/kg was effective in reducing mortality when treatment was initiated at 24 h, 48 h, or, in some cases, 72 h after viral inoculation. In animals treated daily with HDP-CDV or ODE-CDV, virus titers in lung, liver, spleen, kidney, pancreas, salivary gland, and blood were reduced 3 to 5 log 10 -fold, which was comparable to CDV given intraperitoneally. These results indicated that HDP-CDV or ODE-CDV given orally was as effective as parenteral CDV for the treatment of experimental MCMV infection and suggest that further evaluation for use in CMV infections in humans is warranted.Cytomegalovirus (CMV) infections continue to be a major cause of morbidity in solid organ (35) and stem cell recipients (10, 12). The management of these infections has generally been through the use of prophylaxis or prevention therapy with ganciclovir (GCV) (15) or acyclovir (ACV) (3); however, the lack of activity when they are administered orally has limited their use. While the availability of oral ACV (valacyclovir) (29) and GCV (valganciclovir) (32) has broadened the range of choices for treatment or prevention of CMV infections, a number of problems, including neutropenia, nephrotoxicity, and the selection of drug-resistant mutants, remain (6,8,13,27,28,39). Cidofovir (CDV) has greater activity against CMV in vitro and in vivo than any of the other licensed drugs (16,22,23,40) and retains activity against many of the GCV-and foscarnet (PFA)-resistant mutants (4). However, CDV does not have activity when given orally and may also cause severe nephrotoxicity (25, 37). One approach to overcoming the limitation of the lack of activity of CDV given orally has been to prepare prodrugs of CDV that are bioavailable when administered orally. The synthesis of alkylglycerol phosphate or alkylpropyl phosphate esters of ACV, penciclovir, or GCV provided prodrugs that were active when given orally in animal models of herpes simplex virus, murine CMV (MCMV), and woodchuck hepatitis virus infections (17-19). Using similar methodology, a series of ether lipid ester analogs of CDV or cyclic CDV were prepared and evaluated for activity against CMV and poxviruses (4, 24).It has been reported previously that this series of ether lipid ester prodrugs of CDV, partic...

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Section: Discussionmentioning

confidence: 99%

Oral Treatment of Murine Cytomegalovirus Infections with Ether Lipid Esters of Cidofovir

Kern

Collins

Wan

et al. 2004

Antimicrob Agents Chemother

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“…Members of our group and others have used SCID mice inoculated with MCMV as a model for CMV infection in the murine compromised host (13,19,30,42,45). Since SCID mice are profoundly immunocompromised, approximately 1 to 3 PFU will result in a lethal infection.…”

Section: Discussionmentioning

confidence: 99%

Oral Activity of a Methylenecyclopropane Analog, Cyclopropavir, in Animal Models for Cytomegalovirus Infections

Kern

Bidanset

Hartline

et al. 2004

Antimicrob Agents Chemother

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We reported previously that purine 2-(hydroxymethyl)methylenecyclopropane analogs have good activity against cytomegalovirus infection. A second-generation analog, (Z)-9-{[2,2-bis-(hydroxymethyl)cyclopropylidene] methyl}guanine (ZSM-I-62, cyclopropavir [CPV]), has particularly good activity against murine and human cytomegaloviruses (MCMV and HCMV) in vitro. To determine the oral activity of this compound in vivo, BALB/c or severe combined immunodeficient (SCID) mice infected with MCMV and two models using SCID mice implanted with human fetal tissue and subsequently infected with HCMV were used. In MCMV-infected normal mice, CPV at 10 mg/kg of body weight was highly effective in preventing mortality when administered at 24, 48, or 72 h post-viral inoculation and reduced titers of virus in tissues of SCID mice by 2 to 5 log 10 . In one HCMV model, human fetal retinal tissue was implanted into the anterior chamber of the mouse eye and inoculated with the Toledo strain of HCMV, and in the second, human fetal thymus and liver tissues were implanted under the kidney capsule of mice and then inoculated with HCMV. In general, replication of HCMV in both types of implant tissue increased from 7 through 21 to 28 days and then gradually decreased to undetectable levels by 8 weeks postinfection. Oral treatment with 45 or 15 mg of CPV/kg initiated 24 h after infection was highly effective in reducing replication to undetectable levels in both models and was generally more effective than ganciclovir. These data indicate that the methylenecyclopropane analog, CPV, was highly efficacious in these four animal models and should be evaluated for use in HCMV infections in humans.

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“…These models are technically challenging and require human fetal tissue. To overcome some of these difficulties, hollow fiber tubes and agarose plugs carrying HCMV infected cells implanted into SCID mice have also been utilized as models for antiviral evaluation (Allen et al, 1992, Weber et al, 2000Weber et al, 2001). Both models seem less technically demanding than the human transplant models and appear to be useful for antiviral evaluations, but both require surgery whereas the Gelfoam model described here does not.…”

Section: Discussionmentioning

confidence: 99%

A model of human cytomegalovirus infection in severe combined immunodeficient mice

2007

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Animal models for the evaluation of therapies against human cytomegalovirus (HCMV) are limited due to the species-specific replication of CMV. Models utilizing human fetal tissues implanted into SCID mice have been used but tend to be labor intensive and require human tissues. We therefore developed a model using HCMV-infected human foreskin fibroblasts (HFF) seeded onto a biodegradable gelatin matrix (Gelfoam). Infected HFFs are then implanted subcutaneously into SCID mice. We next evaluated two antivirals in this model. Treatment from days 0 to 5 with ganciclovir (GCV) produced a marginally significant reduction in viral titer while treatment from days 0 to 14 resulted in a more significant reduction in viral titers of 1.47 log(10)pfu/ml (P<0.0001). Viral titers were similarly reduced in a group receiving GCV treatment from days 7 to 14 post-implantation (1.50 log(10)pfu/ml, P<0.0001). Cidofovir therapy from days 7 to 14 reduced viral titers by almost 2 log(10)pfu/ml (from 3.51+/-0.31 log(10)pfu/ml in untreated animals to 1.56+/-0.40 log(10)pfu/ml in treated animals, P<0.0001). These results indicate that the Gelfoam-HCMV SCID mouse model is suitable for the in vivo evaluation of new antivirals against HCMV and is simpler and more convenient than previous models.

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A Novel Peptide Aldehyde with Activity against Human Cytomegalovirus in Two Differentin VivoModels

Cited by 8 publications

References 20 publications

Oral Treatment of Murine Cytomegalovirus Infections with Ether Lipid Esters of Cidofovir

Oral Treatment of Murine Cytomegalovirus Infections with Ether Lipid Esters of Cidofovir

Oral Activity of a Methylenecyclopropane Analog, Cyclopropavir, in Animal Models for Cytomegalovirus Infections

A model of human cytomegalovirus infection in severe combined immunodeficient mice

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