Acyclovir diphosphate

The antiviral mechanism of action of acyclovir has been reviewed (72). Acyclovir is converted to the monophosphate in herpes vims-infected cells (but only to a limited extent in uninfected cells) by viral-induced thymidine kinase. It is then further phosphorylated by host cell guanosine monophosphate (GMP) kinase to acyclovir diphosphate [66341 -17-1], which in turn is phosphorylated to the triphosphate by unidentified cellular en2ymes. Acyclovir triphosphate [66341 -18-2] inhibits HSV-1 viral DNA polymerase but not cellular DNA polymerase. As a result, acyclovir is 300 to 3000 times more toxic to herpes vimses in an HSV-infected cell than to the cell itself. Studies have shown that a once-daily dose of acyclovir is effective in prevention of recurrent HSV-2 genital herpes (1). HCMV, on the other hand, is relatively uninhibited by acyclovir. 

The final step added a group that would interact with the phosphate binding site either directly or via electrostatic interactions. We could not use phosphate itself, because phosphate-containing compounds are not metabolically stable and have difficulty passing through cell membranes intact. Acyclovir diphosphate, which is not membrane permeable and is subject to extracellular metabolism, is a good example. 

Hostetler KY, Parker S, Sridhar CN, Martin Ml, Li JL, Stuhmiller LM, van Wijk GMT, van den Bosch H, Gardner MF, Aldem KA et al (1993) Acyclovir diphosphate dimyristoyl-glycerol - a phospholipid prodrug with activity against acyclovir-resistant herpes-simplex virus. Proc Natl Acad Sci USA 90 11835-11839... 

In a related study, Hostetler and coworkers prepared acyclovir diphosphate dimyristoylglycerol (37, R = acyclovir, R = Me(CH2)i2) [54], which... 

Acyclovir Zovirax) is a guanine nucleoside analogue most effective against HSV-1 and HSV-2, but it has some activity against VCV, CMV, and EBV. Valacyclovir (Valtrex) is the L-valine ester prodrug of acyclovir. Acyclovir is converted to its active metabolite via three phosphorylation steps. First, viral thymidine kinase converts acyclovir to acyclovir monophosphate. Next, host cell enzymes convert the monophosphate to the diphosphate and then to the active compound, acyclovir triphosphate. Because viral thymidine kinase has a much greater affinity for acyclovir triphosphate than does mammalian thymidine kinase, acyclovir triphosphate accumulates only in virus-infected cells. 

Cidofovir is an acyclic nucleotide analogue of the monophosphate of cytosine. When phosphoiylated by host cellular enzymes, the active compound cidofovir diphosphate has broad activity against the herpes viruses, including CMV, HSV 1 and 2, VZV, Epstein-Barr virus, and the BK polyomavirus. Cidofovir has primarily been used in the treatment of CMV retinitis in patients who have failed treatment with ganciclovir or foscarnet and in acyclovir-resistant herpes simplex infections. More recently, there is also a growing experience with the use of this medication in kidney transplant patients who have BK virus-associated nephropathy [31], although this interest has been dampened by significant toxicity and only modest clinical activity [32]... 

Chemically stable analogues of acyclovir (26) have been synthesised in an attempt to attain appreciable activity against herpes virus type-1 while allowing their cellular internalisation and bypassing the intracellular activation of acyclovir to its triphosphate derivative required for activity. These compounds are bio-isosteres of acyclovir monophosphate and diphosphate, but are devoid of any appreciable antiviral activity on both HSV-1 and HIV-1. 

Lives. The phosphorylation of acyclovir monophosphate to its diphosphate is catalyzed efficiently only by host cell guanylate kinase". Since the catalyst for BrVdUrd monophosphate (BrVdUMP) phosphorylation was unknown, the viral dThd-dTMP kinase was tested for this ability. 

These results are consistent with anabolism studies with cell cultures. A close analog of BrVdUrd, (E)-5-(2-iodovinyl)-2 -deoxyuridine, was efficiently converted to its monophosphate derivative in cells infected with both HSV-1 and HSV-2. However, a diphosphate (or triphosphate) could only be detected with extracts of cells infected with HSV-1 . The inefficient phosphorylation of BrVdUMP by the dThd-dTMP kinase from HSV-2 correlates well with the observation that replication of HSV-2 is at least 100-fold less sensitive to BrVdUrd than is that of HSV-1 and suggests a cause-and-effect relationship. The sensitivities of the two viruses to acyclovir are about equal. ... 

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