No abstract is provided for this article.
Several guanosine analogues, i.e. acyclovir (and its oral prodrug valaciclovir), penciclovir (in its oral prodrug form, famciclovir) and ganciclovir, are widely used for the treatment of herpesvirus (i.e. HSV-1, HSV-2, VZV and HCMV) infections. In recent years, several new guanosine analogues have been developed, including the 3-membered (cyclopropyl) sugar derivative A-5021 and the 6-membered D- and L-cyclohexenyl derivatives. Prominent features shared by all guanosine analogues are the following. They depend for their phosphorylation on the virus-encoded thymidine kinase (TK), which makes them particularly effective against those viruses (HSV-1, HSV-2 and VZV) that encoded for such TK. They are also active against HCMV, whether or not they are subject of phosphorylation by the HCMV-induced UL97 protein kinase. Their antiviral activity can be markedly potentiated by mycophenolic acid, an IMP dehydrogenase inhibitor, and they hold great promise, not only as antiviral agents for the treatment of herpesvirus infections, but also as antitumor agents for the combined gene therapy/chemotherapy of cancer, provided that (part of) the tumor cells have been transfected by the viral TK gene.
There are a multitude of virus-specific proteins and steps in the replicative cycle of the human immunodeficiency virus (HIV) that could act as targets for potential drugs against the acquired immune deficiency syndrome (AIDS). The reverse transcriptase has proven to be the principal if not the sole target for the anti-HIV activity of 2′,3′-dideoxynucleo-side analogues [i.e. 3′-azido-2′, 3′-dideoxythymidine (AZT), 2′,3′-dideoxycytidine (DDC) and 2′, 3′-didehydro-2′, 3′-dideoxy thymidine (D4T)], following intracellular phosphorylation of these nucleoside analogues to their 5′-triphosphates. Sulfated polysaccharides such as heparin, dextran sulfate and pentosan polysulfate block virus adsorption to the outer cell membrane, which implies that these compounds do not have to be taken up by the cells to achieve their anti-HIV activity. Several other viral processes (i.e. uncoating, integration, transcription and assembly) and viral proteins (i.e. protease, tat protein, rev protein and RNase H) have been identified as attractive targets for antiviral chemotherapy, and an intensive search for specific inhibitors of these functions continues.
Physical and chemical machining (also called non-traditional machining) has revolutionised the manufacturing practice during the second part of the twentiest century. Not only did P&C (Physical and Chemical) manufacturing processes enlarge the range of available machining processes; they also opened the way to machine new hard material. The biggest revolution may have been introduced in the last few years, by the introduction of P&C machining processes that are able to produce parts by adding or growing material to the required product shape.
