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Antimicrobial Agents and Chemotherapy, July 2009, p. 2865-2870, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.00114-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Alkoxyalkyl Esters of 9-(S)-(3-Hydroxy-2-Phosphonomethoxypropyl) Adenine Are Potent and Selective Inhibitors of Hepatitis B Virus (HBV) Replication In Vitro and in HBV Transgenic Mice In Vivo {triangledown}

John D. Morrey,1 Brent E. Korba,2 James R. Beadle,3,4 David L. Wyles,4 and Karl Y. Hostetler3,4*

Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, Utah 84322,1 Division of Molecular Virology and Immunology, Georgetown University Medical Center, Washington, DC 20007,2 San Diego Veterans Medical Research Foundation,3 Department of Medicine, Division of Infectious Disease, University of California, San Diego, La Jolla, California 920934

Received 26 January 2009/ Returned for modification 25 February 2009/ Accepted 16 April 2009

Alkoxyalkyl esters of acyclic nucleoside phosphonates have previously been shown to have increased antiviral activity when they are administered orally in animal models of viral diseases, including lethal infections with vaccinia virus, cowpox virus, ectromelia virus, murine cytomegalovirus, and adenovirus. 9-(S)-(3-Hydroxy-2-phosphonomethoxypropyl)adenine [(S)-HPMPA] was previously shown to have activity against hepatitis B virus (HBV) in vitro. To assess the effect of alkoxyalkyl esterification of (S)-HPMPA, we prepared the hexadecyloxypropyl (HDP), 15-methyl-hexadecyloxypropyl (15M-HDP), and octadecyloxyethyl (ODE) esters and compared their activities with the activity of adefovir dipivoxil in vitro and in vivo. Alkoxyalkyl esters of (S)-HPMPA were 6 to 20 times more active than unmodified (S)-HPMPA on the basis of their 50% effective concentrations in 2.2.15 cells. The increased antiviral activity appeared to be due in part to the increased uptake and conversion of HDP-(S)-HPMPA to HPMPA diphosphate observed in HepG2 cells in vitro. HDP-(S)-HPMPA retained full activity against HBV mutants resistant to lamivudine (L180M, M204V), but cross-resistance to a mutant resistant to adefovir (N236T) was detected. HDP-(S)-HPMPA is orally bioavailable and provides excellent liver exposure to the drug. Oral treatment of HBV transgenic mice with HDP-(S)-HPMPA, 15M-HDP-(S)-HPMPA, and ODE-(S)-HPMPA for 14 days reduced liver HBV DNA levels by roughly 1.5 log units, a response equivalent to that of adefovir dipivoxil.

* Corresponding author. Mailing address: Department of Medicine, Division of Infectious Disease (0676), University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0676. Phone: (858) 552-8585, ext. 2616. Fax: (858) 534-6133. E-mail: khostetler{at}ucsd.edu

{triangledown} Published ahead of print on 27 April 2009.

Antimicrobial Agents and Chemotherapy, July 2009, p. 2865-2870, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.00114-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Botros, S. S., William, S., Beadle, J. R., Valiaeva, N., Hostetler, K. Y. (2009). Antischistosomal Activity of Hexadecyloxypropyl Cyclic 9-(S)-[3-Hydroxy-2-(Phosphonomethoxy)Propyl]Adenine and Other Alkoxyalkyl Esters of Acyclic Nucleoside Phosphonates Assessed by Schistosome Worm Killing In Vitro. Antimicrob. Agents Chemother. 53: 5284-5287 [Abstract] [Full Text]  


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