This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kern, E. R. Articles by Quenelle, D. C. Search for Related Content PubMed PubMed Citation Articles by Kern, E. R. Articles by Quenelle, D. C.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, December 2004, p. 4745-4753, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4745-4753.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Earl R. Kern,^1* Deborah J. Bidanset,¹ Caroll B. Hartline,¹ Zhaohua Yan,² Jiri Zemlicka,² and Debra C. Quenelle¹

University of Alabama School of Medicine, Birmingham, Alabama,¹ Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan²

Received 29 April 2004/ Returned for modification 3 August 2004/ Accepted 17 August 2004

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 log₁₀. 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.

---

* Corresponding author. Mailing address: The University of Alabama at Birmingham, School of Medicine, Department of Pediatrics, Division of Infectious Diseases, 128 CHB, 1600 6th Ave. South, Birmingham, AL 35233. Phone: (205) 934-1990. Fax: (205) 975-1992. E-mail: kern{at}uab.edu.

---

Antimicrobial Agents and Chemotherapy, December 2004, p. 4745-4753, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4745-4753.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Kern, E. R., Kushner, N. L., Hartline, C. B., Williams-Aziz, S. L., Harden, E. A., Zhou, S., Zemlicka, J., Prichard, M. N. (2005). In Vitro Activity and Mechanism of Action of Methylenecyclopropane Analogs of Nucleosides against Herpesvirus Replication. Antimicrob. Agents Chemother. 49: 1039-1045 [Abstract] [Full Text]