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Antimicrobial Agents and Chemotherapy, March 2005, p. 1010-1016, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.1010-1016.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Antiadenovirus Activities of Several Classes of Nucleoside and Nucleotide Analogues

L. Naesens,1* L. Lenaerts,1 G. Andrei,1 R. Snoeck,1 D. Van Beers,2 Antonin Holy,3 Jan Balzarini,1 and Erik De Clercq1

Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium,1 Division of Virology, Hôpital St.-Pierre, Université Libre de Bruxelles, Brussels, Belgium,2 Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic3

Received 27 July 2004/ Returned for modification 16 September 2004/ Accepted 31 October 2004

The absence of any formally licensed antiadenovirus drugs and the increasing incidence of life-threatening adenovirus infections in immunosuppressed patients warrant the development of effective antiadenovirus compounds. A detailed study was performed on the antiadenovirus activities of several classes of nucleoside and nucleotide analogues in human embryonic lung fibroblast cells. The antiadenovirus activities were evaluated by three methods, viz., evaluating the adenoviral cytopathic effect, monitoring cell viability by a colorimetric assay, and real-time PCR quantitation of viral DNA as a direct parameter for virus replication. The most active and selective compounds were the acyclic nucleoside phosphonate analogues cidofovir, its adenine analogue (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], and the new derivative (S)-2,4-diamino-6-[3-hydroxy-2-(phosphonomethoxy)propoxy]pyrimidine [(S)-HPMPO-DAPy]; the N7-substituted acyclic derivative 2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine (S-2242); and the 2',3'-dideoxynucleoside analogues zalcitabine and alovudine. No antiadenovirus activity was observed for the antiviral drugs ribavirin, foscarnet, acyclovir, penciclovir, and brivudin, while ganciclovir displayed modest activity. However, in human osteosarcoma cells transfected with herpes simplex virus thymidine kinase, ganciclovir demonstrated highly potent antiadenovirus activity, suggesting that the efficacy of ganciclovir against adenovirus is limited by inefficient phosphorylation in adenovirus-infected cells, rather than by insufficient inhibition at the viral DNA polymerase level. Collectively, our antiviral data show that the adenovirus DNA polymerase exhibits sensitivity to a relatively broad spectrum of inhibitors and should be studied further as an antiviral target in antiadenovirus drug development programs.

* Corresponding author. Mailing address: Rega Institute for Medical Research, K.U. Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Phone: 32-16-337345. Fax: 32-16-337340. E-mail: lieve.naesens{at}rega.kuleuven.ac.be.

Antimicrobial Agents and Chemotherapy, March 2005, p. 1010-1016, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.1010-1016.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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