Although HHV-6A and -6B are known to replicate preferably in human T-lymphocytes, in vitro infection of several other cell types has been described. Also, the finding that both variants use the ubiquitous molecule CD46 as a membrane receptor fully supports the possibility of a broad cellular tropism. However, productive infection, which requires complete progression through the viral replication cycle, depends on multiple cellular processes. Our studies were aimed at determining the differences in replication efficiency according to the cell type infected and at relating these differences to the sequential transcriptional events preceding DNA replication. A strong expression of immediate-early, early, and late genes was only seen in the T-lymphoblastoma lines. In the other cell lines, there was no clear correlation between the level of transcription and the final outcome of replication. Finally, we investigated the cytopathic effects of HHV-6 on different cell types of neural origin (oligodendrocytes, astrocytes, and neurons) in greater detail, and found that although all three sustained HHV-6 replication, HHV-6A was more neurovirulent than HHV-6B. This was confirmed in primary human oligodendrocyte cultures.
Following the discovery of the first effective antiviral compound (idoxuridine) in 1959, nucleoside analogues, especially acyclovir (ACV) for the treatment of herpesvirus infections, have dominated antiviral therapy for several decades. However, ACV and similar acyclic nucleosides suffer from low aqueous solubility and low bioavailability following oral administration. Derivatives of acyclic nucleosides, typically esters, were developed to overcome this problem and valaciclovir, the valine ester of ACV, was among the first of a new series of compounds that were readily metabolized upon oral administration to produce the antiviral nucleoside in vivo, thus increasing the bioavailility by several fold. Concurrently, famciclovir was developed as an oral formulation of penciclovir. These antiviral 'prodrugs' thus established a principle that has led to many successful drugs including both nucleoside and nucleotide analogues for the control of several virus infections, notably those caused by herpes-, retro- and hepatitisviruses. This review will chart the origins and development of the most important of the antiviral prodrugs to date.
Picornaviruses cover a large family of pathogens that have a major impact on human but also on veterinary health. Although most infections in man subside mildly or asymptomatically, picornaviruses can also be responsible for severe, potentially life-threatening disease. To date, no therapy has been approved for the treatment of picornavirus infections. However, efforts to develop an antiviral that is effective in treating picornavirus-associated diseases are ongoing. In 2007, Schering-Plough, under license of ViroPharma, completed a phase II clinical trial with Pleconaril, a drug that was originally rejected by the FDA after a New Drug Application in 2001. Rupintrivir, a rhinovirus protease inhibitor developed at Pfizer, reached clinical trials but was recently halted from further development. Finally, Biota's HRV drug BTA-798 is scheduled for phase II trials in 2008. Several key steps in the picornaviral replication cycle, involving structural as well as non-structural proteins, have been identified as valuable targets for inhibition. The current review aims to highlight the most important developments during the past decades in the search for antivirals against picornaviruses.
A new class of acyclic adenosine analogues is described which exhibit broad-spectrum antiviral activity and are apparently targeted at S-adenosyl-L-homocysteine hydrolase. The compounds are all alkyl (i.e., methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methylpropyl, tert-butyl, 1-pentyl, 3-methylbutyl, 1-octyl, 2-hydroxyethyl, 2-methoxyethyl, furylmethyl, cyclohexyl) esters of (RS)-3-adenin-9-yl-2-hydroxypropanoic acid. They are inhibitory to a broad variety of viruses, including vesicular stomatitis, vaccinia, reo, parainfluenza, and measles, and, with one exception (the furylmethyl ester), nontoxic to the host cell at antivirally active concentrations. It is postulated that the alkyl esters are as such taken up by the cells and hydrolyzed within the cells to release the parent compound, 3-adenin-9-yl-2-hydroxypropanoic acid.
