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J Med Chem. 2009 Sep 10;52(17):5520-30. doi: 10.1021/jm9007856.

The application of phosphoramidate protide technology to acyclovir confers anti-HIV inhibition.

Author information

1
Welsh School of Pharmacy, Cardiff University, Cardiff, UK.

Abstract

Recently, it has been reported that phosphorylated acyclovir (ACV) inhibits human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in a cell-free system. To deliver phosphorylated ACV inside cells, we designed ACV monophosphorylated derivatives using ProTide technology. We found that the L-alanine derived ProTides show anti-HIV activity at noncytotoxic concentrations; ester and aryl variation was tolerated. ACV ProTides with other amino acids, other than L-phenylalanine, showed no detectable activity against HIV in cell culture. The inhibitory activity of the prodrugs against herpes simplex virus (HSV) types -1 and -2 and thymidine kinase-deficient HSV-1 revealed different structure-activity relationships but was again consistent with successful nucleoside kinase bypass. Enzymatic and molecular modeling studies have been performed in order to better understand the antiviral behavior of these compounds. ProTides showing diminished carboxypeptidase lability translated to poor anti-HIV agents and vice versa, so the assay became predictive.

PMID:
19645484
PMCID:
PMC2748767
DOI:
10.1021/jm9007856
[Indexed for MEDLINE]
Free PMC Article

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