The metabolism and mode of action of penciclovir [9-(4-hydroxy-3-hydroxymethylbut-1-yl) Penciclovir, through its triphosphate ester (Fig. 1), is a potent and selective antiherpesvirus agent, particularly against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2, respectively) and varicella-zoster virus (VZV) (9, 3, 4). Previous studies (3,4,9) showed that penciclovir has a spectrum of antiviral activity similar to that of acyclovir, but that penciclovir has an antiviral effect that is longer lasting than that of acyclovir. This may relate to the efficient trapping of the active metabolite, the triphosphate ester of penciclovir, within virus-infected cells (22). Penciclovir and its well-absorbed oral form, famciclovir (23), are undergoing clinical trials for their efficacies not only against HSV-1 infections but also against HSV-2 and VZV infections. There may be appreciable quantitative differences between the rates of metabolism of penciclovir in HSV-and VZVinfected cells. The uptake and phosphorylation in VZVinfected cells has been reported for a pyrimidine analog, 1-3-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (25), and for acyclovir at 250 ,uM (1), but we are unaware of any reports of similar work with acycloguanosine analogs at clinically relevant concentrations. Only recently (2) have we been able to provide a clear indication that penciclovir has prolonged antiviral activity in VZV-infected cells. Therefore, it was of particular interest to determine whether penciclovir-triphosphate (PCV-TP) is formed and then remains at high concentrations within VZV-infected cells following treatment of the cell culture for a short period.In this report, we describe the continuation of our studies * Corresponding author.of the mode of action of penciclovir in comparison with that of acyclovir. We investigated the phosphorylation of the acyclonucleosides in HSV-2-and VZV-infected human cells and the stability of PCV-TP in these cells. Also, we report results of our initial studies in which we investigated the effect of PCV-TP on HSV and VZV DNA polymerases. The phosphate esters of penciclovir, unlike those of acyclovir, are chiral with the possibility that the (R) and (S) enantiomers of the triphosphate ester are formed, although the (S) enantiomer is the predominant form in HSV-1-infected cells
The metabolism and mode of action of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (BRL 39123) were studied in herpes simplex virus type 1 (HSV-1)-infected and uninfected MRC-5 cells and compared with those of acyclovir. In uninfected cells incubated with 10 ,uM acyclonucleoside for 4 h, no phosphorylation of either BRL 39123 or acyclovir was detected. In contrast, in HSV-1-infected cells, both BRL 39123 and acyclovir were phosphorylated up to the triphosphate esters. Phosphorylation of BRL 39123 occurred much more rapidly and proceeded to a greater extent than did that of acyclovir. Furthermore, following the removal of acyclonucleoside from the culture medium, the intracellular triphosphate ester of BRL 39123 was much more stable than was that of acyclovir, the half-lives being about 10 and 0.7 h, respectively. BRL 39123 treatment effectively inhibited the formation of HSV-1 DNA in infected MRC-5 cells, 50% inhibitory concentrations of BRL 39123 and acyclovir being 0.04 ,Lg/ml (0.16 ,uM) and 0.15 ,ug/ml (0.67 ,IM), respectively. In addition, BRL 39123 was shown to be more effective than acyclovir at inhibiting viral DNA synthesis following short treatment times, presumably reflecting the greater stability of BRL 39123 triphosphate. Neither BRL 39123 nor acyclovir inhibited cellular DNA synthesis in uninfected cells at concentrations of up to 100 jig/ml.The discovery of the selective antiherpesvirus activity of acyclovir (16) and its subsequent clinical use for herpes genitalis, herpes labialis, and herpes zoster have stimulated much interest in other acyclonucleosides. Following improved synthesis (10, 11), the virological evaluation (2, 3) of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (BRL 39123) indicated that this compound had a spectrum of antiviral activity similar to that of acyclovir and a similar low toxicity for uninfected cells. However, it had a more persistent antiviral effect than did acyclovir. Larsson et al. (14) showed that this acyclonucleoside, at a concentration of 250 ,uM, was readily phosphorylated by herpes simplex virus type 1 (HSV-1) thymidine kinase but was not phosphorylated by the thymidine kinase from Vero cells. This result suggests that the antiviral activity of BRL 39123 may occur via a phosphorylated metabolite of BRL 39123.In this paper, we describe the phosphorylation kinetics in human cells infected with HSV-1 of BRL 39123 at concentrations (10 and 1 jiM) that have been achieved in the plasma of volunteers
Famciclovir is the oral form of penciclovir, a highly selective antiherpesvirus agent. Both famciclovir and penciclovir are being evaluated in clinical studies. This review covers the conversion of famciclovir to penciclovir, the formation and stability of penciclovir-triphosphate, its effect on herpesvirus DNA polymerases and the inhibition of viral DNA synthesis in cell cultures. The conversion of famciclovir into penciclovir is described, emphasising work with human tissues and including the elucidation of the structures of its chiral monoacetylated derivatives. To reflect its metabolism during oral absorption, famciclovir was incubated in duodenal contents, extracts of intestinal wall and liver, and in blood. The major metabolic route was by de-acetylation followed by oxidation of the purine to form penciclovir. This work with human tissues was predictive of the major metabolic pathway in humans. Penciclovir is phosphorylated much more efficiently than acyclovir in herpesvirus-infected cells yet the host cell kinases phosphorylate the two compounds to a small but comparable extent. This highly preferential metabolism in herpesvirus infected cells is a major factor in its selective antiviral activity. The ( S) enantiomer of penciclovir-triphosphate is the major metabolite and it has good stability in HSV-1, HSV-2, and VZV infected cells. At the high concentrations found in infected cells, penciclovir-triphosphate was an effective inhibitor of viral DNA polymerases and of viral DNA synthesis. The efficient entrapment of the active moiety can account for the markedly better antiviral activity of penciclovir than acyclovir when infected cell cultures were treated for a short time. Such assays reflect more closely the clinical situation after oral dosing than do standard assays in which the test compounds are present continuously. The role of these studies in compound selection and development is discussed.
The SARS-CoV-2 pandemic has affected more than 185 million people worldwide resulting in over 4 million deaths. To contain the pandemic, there is a continued need for safe vaccines that provide durable protection at low and scalable doses and are easily delivered. Here, AAVCOVID-1, an adeno-associated viral (AAV), Spike gene-based vaccine candidate demonstrates potent immunogenicity in mouse and nonhuman primates following a single injection and confers complete protection from SARS-CoV-2 challenge in macaques. Peak neutralizing antibody titers are sustained at 1 year and complemented by functional memory T-cell responses. The AAVCOVID vector has no relevant pre-existing immunity in humans, does not elicit cross-reactivity to common AAVs used in gene therapy, and its persistence and expression wanes following injection. The single, low dose requirement, high yield manufacturability, and 1-month stability for storage at room-temperature may make this technology well-suited to support effective immunization campaigns for emerging pathogens on a global scale.
Background Herpesviruses notably establish lifelong infections, with latency and reactivation. Many of the known human herpesviruses infect large proportions of the population worldwide. Treatment or prevention of herpes infections and recurrent disease still pose a challenge in the 21st century. Sources of data Original papers and review articles, meeting abstracts, a book (Clinical Virology; DD Richman, RJ Whitley & FG Hayden eds) and company web sites. Areas of agreement For herpes simplex types 1 and 2 and for varicella zoster, acyclovir (ACV; now increasingly replaced by its prodrug valacyclovir, VACV) and famciclovir (FCV) have greatly reduced the burden of disease and have established a remarkable safety record. Drug-resistance, in the otherwise healthy population, has remained below 0.5% after more that 20 years of antiviral use. In immunocompromised patients, drug resistance is more common and alternative drugs with good safety profiles are desirable. For human cytomegalovirus disease, which occurs in immunocompromised patients, ganciclovir and increasingly its prodrug valganciclovir are the drugs of choice. However, alternative drugs, with better safety, are much needed. Areas of controversy Various questions are highlighted. Should the new 1-day therapies for recurrent herpes labialis and genital herpes replace the current standard multi-day therapies? The marked differences between VACV and FCV (e.g. triphosphate stability, effect on latency) may not yet be fully exploited? Do current antivirals reduce post-herpetic neuralgia (PHN)? For immunocompromised patients with varicella zoster virus (VZV) disease, should the first-line treatment be FCV, not ACV or VACV? Should there be more support to explore new avenues for current antivirals, for example in possibly reducing herpes latency or Alzheimer's disease (AD)? Should primary Epstein-Barr virus (EBV) disease in adolescents be treated with antivirals? How can new compounds be progressed when the perceived market need is small but the medical need is great. FCV was reclassified from prescription-only to pharmacist-controlled for herpes labialis in New Zealand in 2010; should this be repeated more widely? This article reviews new drugs in clinical trials and highlights some of the problems hindering their progress.
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