Bis(isopropyloxymethylcarbonyl) 9-R-(2-phosphonomethoxypropyl)adenine [bis(POC)PMPA] has been identified as a novel prodrug of PMPA. The anti-human immunodeficiency virus activity of bis(POC)PMPA was >100-fold greater than that of PMPA in both an established T-cell line and primary peripheral blood lymphocytes. This improved efficacy was shown to be due to a rapid intracellular uptake of the prodrug resulting in an increased intracellular accumulation of PMPA diphosphate (PMPApp), the pharmacologically active metabolite. PMPApp levels in bis(POC)PMPA-treated cells exceeded by >1,000-fold the levels seen in cells treated with unmodified PMPA in both resting and activated peripheral blood lymphocytes. Significant differences in the intracellular catabolism of PMPA metabolites were noted between the resting and activated lymphocytes. The half-life for the disappearance of PMPApp, derived from either bis(POC)PMPA or PMPA, was 12 to 15 h in the activated lymphocytes and 33 to 50 h in the resting lymphocytes. This long persistence of PMPApp, particularly in resting lymphocytes, may be unique to the nucleoside phosphonate analogs and indicates that effective levels of the active metabolite can be achieved and maintained with relatively infrequent administration of the parent drug.

https://aac.asm.org/content/aac/42/3/612.full.pdf

Anti-Human Immunodeficiency Virus Activity and Cellular Metabolism of a Potential Prodrug of the Acyclic Nucleoside Phosphonate 9-R-(2-Phosphonomethoxypropyl)adenine (PMPA), Bis(isopropyloxymethylcarbonyl)PMPA

Human cytomegalovirus encodes an unusual protein kinase, UL97, that activates the established antiviral drug ganciclovir and is specifically inhibited by a new antiviral drug, maribavir. We used maribavir and a UL97 null mutant, which is severely deficient in viral replication, to determine what stage of virus infection critically requires UL97. Compared with wild-type virus, there was little or no decrease in immediate-early gene expression, viral DNA synthesis, late gene expression, or packaging of viral DNA into nuclease-resistant structures in mutant-infected or maribavir-treated cells under conditions where the virus yield was severely impaired. Electron microscopy studies revealed similar proportions of various capsid forms, including DNA-containing capsids, in the nuclei of wild-type- and mutant-infected cells. However, capsids were rare in the cytoplasm of mutant-infected or maribavir-treated cells; the magnitudes of these decreases in cytoplasmic capsids were similar to those for virus yield. Thus, genetic and pharmacological evidence indicates that UL97 is required at the stage of infection when nucleocapsids exit from the nucleus (nuclear egress), and this poorly understood stage of virus infection can be targeted by antiviral drugs. Understanding UL97 function and maribavir action should help elucidate this interesting biological process and help identify new antiviral drug targets for an important pathogen in immunocompromised patients.

The human cytomegalovirus UL97 protein kinase, an antiviral drug target, is required at the stage of nuclear egress.

The synthesis of the potent anti-herpes virus agent, E-5(2-bromovinyl)-2′-deoxyuridine and related compounds

Discovery and development of BVDU (brivudin) as a therapeutic for the treatment of herpes zoster.

Protein kinases play a crucial role in the regulation of protein function through phosphorylation of targeted proteins. Human cytomegalovirus (HCMV) encodes many phosphorylated proteins and at least one protein kinase, the product of the UL97 open reading frame (ORF) (6, 13). UL97 is most closely related in sequence to certain protein kinases encoded by various herpesviruses, which collectively form the HvUL protein kinase family (18). These enzymes share many motifs typical of protein kinases but are relatively divergent. The protein kinase motifs of UL97 are even more divergent than those of other family members (6). Biochemically, UL97 is rather unusual in that it can phosphorylate nucleoside analogs such as the antiviral drugs acyclovir and ganciclovir (30). Indeed, phosphorylation of ganciclovir by UL97 is responsible for much of the antiviral selectivity of this drug (29). In vitro, UL97 can autophosphorylate (1, 13). It can also phosphorylate certain exogenous protein and peptide substrates (1, 2, 8, 13; P. B. Sethna, M. G. Davis, C. L. Talarico, W. H. Miller, K. Blackburn, W. A. Burhart, M. B. Moyer, K. K. Biron, and R. J. Harvey, submitted for publication). With these more conventional substrates, it is rather specific. For example, it phosphorylates histones only on particular serine residues (2), but it does not phosphorylate various other proteins, for example, glutathione S-transferase (GST) (8) or various serine/threonine containing peptides (2). Its specificity appears to be due in part to an unusual preference for basic residues five positions downstream of the phosphorylation site (1, 2).

UL97 is important, but not completely essential, for viral replication (25). It has been reported to have roles at the stages of DNA replication, DNA encapsidation, and/or nuclear egress (3, 15, 33). An understanding of how UL97 functions during viral replication would be greatly aided by identifying its natural substrates. An initial step in that direction made use of maribavir (also known as 1263W94), a potent inhibitor of HCMV replication in tissue culture that acts via inhibition of UL97 (3). When lysates from wild-type (wt) HCMV-infected cells were incubated with radiolabeled ATP, the inclusion of maribavir reduced the phosphorylation of several proteins; the phosphorylation of these proteins was not reduced by maribavir in lysates from cells infected with a maribavir-resistant mutant (Sethna et al., submitted). One of these proteins was UL44, a phosphoprotein encoded by the HCMV UL44 ORF, also known as pp52 and ICP36 (5, 11, 16). UL44 is essential for HCMV DNA replication and appears to serve as the processivity subunit of the viral DNA polymerase (10, 24, 28, 32, 35), which might be relevant to the role of UL97 in viral infection. However, it was not shown that UL97 directly phosphorylates UL44, nor has there been evidence that UL97 is required for the normal phosphorylation of any viral protein in infected cells. We therefore sought to determine if UL44 is a substrate for UL97 in vitro and in infected cells.

The Human Cytomegalovirus UL44 Protein Is a Substrate for the UL97 Protein Kinase

The synthesis and properties of some antiviral nucleosides

Synthesis and biological evaluation of bicyclic furano pyrimidine nucleosides as inhibitors of human cytomegalovirus

Anti-retrovirus activity and pharmacokinetics in mice of bis(POC)-PMPA, the bis(isopropyloxycarbonyloxymethyl) oral prodrug of PMPA

(D)‐ and (L)‐Cyclohexenyl‐G, a New Class of Antiviral Agents: Synthesis, Conformational Analysis, Molecular Modeling, and Biological Activity

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The synthesis and properties of some antiviral nucleosides

Synthesis and biological evaluation of bicyclic furano pyrimidine nucleosides as inhibitors of human cytomegalovirus

Anti-retrovirus activity and pharmacokinetics in mice of bis(POC)-PMPA, the bis(isopropyloxycarbonyloxymethyl) oral prodrug of PMPA

(D)‐ and (L)‐Cyclohexenyl‐G, a New Class of Antiviral Agents: Synthesis, Conformational Analysis, Molecular Modeling, and Biological Activity