Human Cytomegalovirus Activation Research Articles

Synthesis and Anti-Herpes Activity of a Series of Indolizines

A systematic screening study identified 2-phenyl-indolizine [1] as having significant human cytomegalovirus (HCMV) activity (IC50 = 7-19 μM). Preliminary mode of action studies on infected cells treated with [1] indicated supression of HCMV-related polypeptides with little effect on the host cells. A series of analogues were synthesized, some of which showed improved HCMV activity although with lower therapeutic indices than [1]. Several analogues demonstrated significant varicella zoster virus activity, with 2-(4-cyanophenyl)indolizine [5] having an IC50 of 5 μM and a therapeutic index of 20 over cell toxicity in the MRC 5 cell line.

Review of research leading to new anti-herpesvirus agents in clinical development: Valaciclovir hydrochloride (256u, the L-valyl ester of acyclovir) and 882c, a specific agent for varicella zoster virus

Research leading to the new anti-herpesvirus compounds discussed here has come from three approaches. The first approach was directed towards improving the bioavailability of acyclovir by examining the potential of a variety of prodrugs, leading to the new compound valaciclovir hydrochloride. The second approach was to examine a large number of 5-substituted pyrimidines for activity against those viruses which were not as potently inhibited by acyclovir as are herpes simplex viruses, i.e., varicella zoster virus (VZV) and human cytomegalovirus (HCMV). This research led to the new chemical entity 882C for VZV. A third approach has been to examine drug combinations with acyclovir. This research led to the compound 348U, an inhibitor of herpes simplex virus ribonucleotide reductase which acts synergistically in combination with acyclovir. This manuscript will focus on the first two approaches leading to new compounds valaciclovir hydrochloride and 882C since Dr. Safrin details such background for 348U/acyclovir. Attempts to improve the bioavailability of acyclovir began a decade ago. Early prodrugs were compounds with alterations in the 6-substituent of the purine ring of acyclovir. The 6-amino congener required the cellular enzyme adenosine deaminase for conversion to acyclovir and the 6-deoxycongener was dependent on cellular xanthine oxidase for conversion. Neither of these prodrugs had a chronic toxicity profile in laboratory animals as good as acyclovir. Efforts were directed towards simpler esters and 18 amino acid esters were made. The pharmacokinetic profile of each prodrug was determined in rats by measuring the recovery of acyclovir in urine after oral dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Transcriptional activation of cellular oncogenes fos, jun, and myc by human cytomegalovirus

The mechanisms responsible for the human cytomegalovirus (HCMV)-induced increase in cellular oncogene RNAs for c-jun, c-fos, and c-myc in human embryo lung cells (I. Boldogh, S. AbuBakar, and T. Albrecht, Science 247:561-564, 1990) were investigated. Results of transcription assays indicated that the rapid increase in RNA levels for the above-noted oncogenes was controlled at the transcriptional level and was related to enhanced transcription. The maximum rates of transcription for c-jun and c-fos genes occurred at 40 min postinfection, while for the c-myc gene the maximum rate occurred at about 60 min. The magnitude of HCMV-induced activation of these cellular genes was similar to the activation induced by serum. The half-lives of the cellular oncogenes showed similar decay rates after either serum or HCMV activation when measured by dactinomycin chase. The half-life for c-fos or c-jun was about 20 min, and that for c-myc was about 40 min. Furthermore, inhibition of the RNA increase by dactinomycin or by alpha-amanitin suggested that the increase in RNA levels was due to an increase in the transcriptional activity of oncogenes triggered by HCMV.