PubMed · 14993516
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Linda A Waggoner-Fountain, Leigh B Grossman. 2004. Herpes simplex virus.. https://doi.org/10.1542/pir.25-3-86
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Nucleoside analogs used in antiviral therapies need to be phosphorylated to their tri-phospho counterparts in order to be active on their cellular target. Human phosphoglycerate kinase (hPGK) was recently reported to participate in the last step of phosphorylation of cytidine L-nucleotide derivatives [Krishnan PGE, Lam W, Dutschman GE, Grill SP, Cheng YC. Novel role of 3-phosphoglycerate kinase, a glycolytic enzyme, in the activation of L-nucleoside analogs, a new class of anticancer and antiviral agents. J Biol Chem 2003;278:36726-32]. In the present work, we extended the enzymatic study of human PGK specificity to purine and pyrimidine nucleotide derivatives in both D- and L-configuration. Human PGK demonstrated catalytic efficiencies in the 10(4)-10(5)M(-1)s(-1) range for purine ribo-, deoxyribo- and dideoxyribonucleotide derivatives, either in D- or L-configuration. In contrast, it was poorly active with natural pyrimidine D-nucleotides (less than 10(3)M(-1)s(-1)). Pyrimidine L-enantiomers, which are promising therapeutic analogs against B hepatitis, were 2-25 times better substrates than their D-counterparts. The broad specificity of substrate of human PGK suggests that this enzyme may be involved in the cellular activation of several antiviral nucleoside analogs including dideoxyinosine, acyclovir, L-2'-deoxycytosine and L-2'-deoxythymidine.
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Three randomized controlled trials of valacyclovir for the management of recurrences of genital herpes in HIV-infected persons were conducted between 1991 and 2002. One study evaluated episodic therapy for the treatment of genital herpes, and 2 studies evaluated continuous suppressive therapy. Valacyclovir at 1000 mg twice daily for 5 days was comparable to acyclovir at 200 mg 5 times daily in accelerating healing of a single episode of genital herpes (hazard ratio, 1.0; 95% confidence interval [CI], 0.8-1.2; P=.89). Valacyclovir at 500 mg twice daily was effective in preventing or delaying recurrences of genital herpes compared with placebo (hazard ratio, 0.20; 95% CI, 0.13-0.30; P<.001) and with valacyclovir at 1000 mg once daily (hazard ratio, 0.56; 95% CI, 0.40-0.80; P=.001), in 6-month and 48-week studies, respectively. The safety profile of valacyclovir was similar to that of acyclovir. Valacyclovir is well tolerated, safe, and effective for the treatment and suppression of recurrent genital herpes in human immunodeficiency virus-infected persons.