Abstract
The acyclic nucleotide analog (S)-1-[(3-hydroxy-2-phosphonylmethoxy)propyl]cytosine (HPMPC) is a potent and selective inhibitor of herpesviruses. Cells preincubated with HPMPC are refractory to herpes simplex virus type 2 (HSV-2) infection for several days after removal of the drug from the medium. A single administration of 30 mg of HPMPC per kg of body weight 4 days prior to virus infection intraperitoneally with HSV-2 (strain G) completely protected mice from death, and the protective effect was dose dependent. HPMPC was equally efficacious in protecting mice when the same total amount of the drug was administered as a single dose as when it was given daily in several smaller doses (5 mg/kg with treatment initiation at 3 h postinfection [p.i.], 90 versus 80% survival, respectively). In contrast, ganciclovir [9(1,3-dihydroxy-2-propoxymethyl)guanine] was more efficacious when it was given daily than it was when it was given less than daily in a late stage of HSV-2 infection (100 mg/kg; when mice were treated 96 h p.i., 80 versus 50% survival, respectively; when mice were treated 120 h p.i., 60 versus 20% survival, respectively). Therefore, single doses of HPMPC were more effective than ganciclovir in protecting mice from death (80 versus 20% survival, respectively; P less than 0.05), whereas there was no difference when the drugs were given daily (50 versus 60% survival, respectively). Our studies suggest a potential of HPMPC for conventional and prophylactic treatments of herpesvirus infections with infrequent drug administration.
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- Bronson J. J., Ho H. T., De Boeck H., Woods K., Ghazzouli I., Martin J. C., Hitchcock M. J. Biochemical pharmacology of acyclic nucleotide analogues. Ann N Y Acad Sci. 1990;616:398–407. doi: 10.1111/j.1749-6632.1990.tb17859.x. [DOI] [PubMed] [Google Scholar]
- Datema R., Ericson A. C., Field H. J., Larsson A., Stenberg K. Critical determinants of antiherpes efficacy of buciclovir and related acyclic guanosine analogs. Antiviral Res. 1987 Jul;7(6):303–316. doi: 10.1016/0166-3542(87)90013-1. [DOI] [PubMed] [Google Scholar]
- Field A. K., Davies M. E., DeWitt C., Perry H. C., Liou R., Germershausen J., Karkas J. D., Ashton W. T., Johnston D. B., Tolman R. L. 9-([2-hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine: a selective inhibitor of herpes group virus replication. Proc Natl Acad Sci U S A. 1983 Jul;80(13):4139–4143. doi: 10.1073/pnas.80.13.4139. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Field H. J., Anderson J. R., Efstathiou S. A quantitative study of the effects of several nucleoside analogues on established herpes encephalitis in mice. J Gen Virol. 1984 Apr;65(Pt 4):707–719. doi: 10.1099/0022-1317-65-4-707. [DOI] [PubMed] [Google Scholar]
- Kern E. R. Acyclovir treatment of experimental genital herpes simplex virus infections. Am J Med. 1982 Jul 20;73(1A):100–108. doi: 10.1016/0002-9343(82)90073-0. [DOI] [PubMed] [Google Scholar]
- Kern E. R., Richards J. T., Overall J. C., Jr, Glasgow L. A. Alteration of mortality and pathogenesis of three experimental Herpesvirus hominis infections of mice with adenine arabinoside 5'-monophosphate, adenine arabinoside, and phosphonoacetic acid. Antimicrob Agents Chemother. 1978 Jan;13(1):53–60. doi: 10.1128/aac.13.1.53. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kim C. U., Luh B. Y., Misco P. F., Bronson J. J., Hitchcock M. J., Ghazzouli I., Martin J. C. Acyclic purine phosphonate analogues as antiviral agents. Synthesis and structure-activity relationships. J Med Chem. 1990 Apr;33(4):1207–1213. doi: 10.1021/jm00166a019. [DOI] [PubMed] [Google Scholar]
- Li S. B., Yang Z. H., Feng J. S., Fong C. K., Lucia H. L., Hsiung G. D. Activity of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) against guinea pig cytomegalovirus infection in cultured cells and in guinea pigs. Antiviral Res. 1990 May;13(5):237–252. doi: 10.1016/0166-3542(90)90069-j. [DOI] [PubMed] [Google Scholar]
- Smee D. F., Boehme R., Chernow M., Binko B. P., Matthews T. R. Intracellular metabolism and enzymatic phosphorylation of 9-(1,3-dihydroxy-2-propoxymethyl)guanine and acyclovir in herpes simplex virus-infected and uninfected cells. Biochem Pharmacol. 1985 Apr 1;34(7):1049–1056. doi: 10.1016/0006-2952(85)90608-2. [DOI] [PubMed] [Google Scholar]
- Smee D. F., Campbell N. L., Matthews T. R. Comparative anti-herpesvirus activities of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, acyclovir, and two 2'-fluoropyrimidine nucleosides. Antiviral Res. 1985 Oct;5(5):259–267. doi: 10.1016/0166-3542(85)90040-3. [DOI] [PubMed] [Google Scholar]