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Antimicrobial Agents and Chemotherapy, February 2007, p. 611-615, Vol. 51, No. 2
0066-4804/07/$08.00+0     doi:10.1128/AAC.00444-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Antiviral Activities of Novel 5-Phosphono-Pent-2-en-1-yl Nucleosides and Their Alkoxyalkyl Phosphonoesters{triangledown}

Hyunah Choo,1,{dagger} James R. Beadle,1 Earl R. Kern,2 Mark N. Prichard,2 Kathy A. Keith,2 Caroll B. Hartline,2 Julissa Trahan,1 Kathy A. Aldern,1 Brent E. Korba,3 and Karl Y. Hostetler1*

Department of Medicine, Division of Infectious Disease, University of California, San Diego, La Jolla, California 92093-0676, and the Veterans Medical Research Foundation, San Diego, California 92161,1 Department of Pediatrics, University of Alabama School of Medicine, Birmingham, Alabama 35233,2 Division of Molecular Virology and Immunology, Georgetown University Medical Center, Rockville, Maryland 208503

Received 10 April 2006/ Returned for modification 26 May 2006/ Accepted 31 October 2006

Three acyclic nucleoside phosphonates are currently approved for clinical use against infections caused by cytomegalovirus (Vistide), hepatitis B virus (Hepsera), and human immunodeficiency virus type 1 (Viread). This important antiviral class inhibits viral polymerases after cellular uptake and conversion to their diphosphates, bypassing the first phosphorylation, which is required for conventional nucleoside antivirals. Small chemical alterations in the acyclic side chain lead to marked differences in antiviral activity and the spectrum of activity of acyclic nucleoside phosphonates against various classes of viral agents. We synthesized a new class of acyclic nucleoside phosphonates based on a 5-phosphono-pent-2-en-1-yl base motif in which the oxygen heteroatom usually present in acyclic nucleoside phosphonates has been replaced with a double bond. Since the intrinsic phosphonate moiety leads to low oral bioavailability and impaired cellular penetration, we also prepared the hexadecyloxypropyl esters of the 5-phosphono-pent-2-en-1-yl nucleosides. Our earlier work showed that this markedly increases antiviral activity and oral bioavailability. Although the 5-phosphono-pent-2-en-1-yl nucleosides themselves were not active, the hexadecyloxypropyl esters were active against DNA viruses and hepatitis B virus, in vitro. Notably, the hexadecyloxypropyl ester of 9-(5-phosphono-pent-2-en-1-yl)-adenine was active against hepatitis B virus mutants resistant to lamivudine, emtricitabine, and adefovir.

* Corresponding author. Mailing address: Department of Medicine (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: khostetl{at}ucsd.edu.

{triangledown} Published ahead of print on 27 November 2006.

{dagger} Present address: Life Sciences Division, Korea Institute of Science and Technology, Seoul 136-791, Korea.

Antimicrobial Agents and Chemotherapy, February 2007, p. 611-615, Vol. 51, No. 2
0066-4804/07/$08.00+0     doi:10.1128/AAC.00444-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Painter, G. R., Almond, M. R., Trost, L. C., Lampert, B. M., Neyts, J., De Clercq, E., Korba, B. E., Aldern, K. A., Beadle, J. R., Hostetler, K. Y. (2007). Evaluation of Hexadecyloxypropyl-9-R-[2-(Phosphonomethoxy)Propyl]- Adenine, CMX157, as a Potential Treatment for Human Immunodeficiency Virus Type 1 and Hepatitis B Virus Infections. Antimicrob. Agents Chemother. 51: 3505-3509 [Abstract] [Full Text]  


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