It is not yet clear to what extent depletion of intracellular GTP pools contributes to the antiviral activity of ribavirin. Therefore, the antiviral activities of (i) ribavirin, (ii) its 5-ethynyl analogue, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR), and (iii) mycophenolic acid (MPA) (a compound that inhibits only cellular IMP dehydrogenase activity) were studied on the replication of flaviviruses and paramyxoviruses. In addition, the effects of these three compounds on intracellular GTP pools were assessed. A linear correlation was observed over a broad concentration range between the antiviral activities of ribavirin, EICAR, and MPA and the effects of these compounds on GTP pool depletion. When the 50% effective concentrations (EC50s) for the antiviral activities of ribavirin, EICAR, and MPA were plotted against the respective EC50 values for GTP pool depletion, a linear correlation was calculated. These data provide compelling evidence that the predominant mechanism of action of ribavirin in vitro against flavi- and paramyxoviruses is based on inhibition of cellular IMP dehydrogenase activity.
The synthesis of three new monopyrazole analogues of the antiviral compound distamycin A is reported. Suitably protected 4-amino-1-methylpyrrole-2-carboxylic acid and 3-amino-1-methylpyrazole-5-carboxylic acid derivatives were chosen as starting materials. The construction of the trimeric polyamide framework was accomplished by assembly of the monomeric precursors under condensing conditions by analogy with our previous methodology, although with significant improvements in some pivotal steps. After chromatographic purification and spectroscopic characterisation, the analogues were assayed for antiviral activity. Compounds 7a-c inhibited vaccinia virus at a concentration similar to or lower than distamycin A and the related antibiotic netropsin. Analogues 7b and 7c exhibited an antiviral effect comparable to those of distamycin A and netropsin against HSV-1 and HSV-2, whereas their antiviral activity against several other viruses including HIV-1 and HIV-2 was somewhat lower. The cellular toxicity of 7a-c toward different host cell types proved to be of similar magnitude or lower than those of distamycin A and netropsin.
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IDU (5-iodo-2'-deoxyuridine), BVDU [(E)-5-(2-bromovinyl)-2'-deoxyuridine] and placebo ointments were studied for their effects on experimental herpes simplex (type 1) keratoconjuncitivitis in rabbits. When treatment was begun 65 h after virus inoculation, both BVDU and IDU prevented development of keratitis. Both BVDU and IDU were also effective in suppressing the severity of conjunctivitis, and in this respect, BVDU proved significantly better than IDU. When treatment was started 110 h after virus inoculation, BVDU proved significantly better than IDU in promoting healing of established keratitis.
Summary The paper gives a state-of-the-art overview of so called rapid prototyping techniques, like stereolithography, selective laser sintering, ballistic particle manufacturing and others. These are new manufacturing techniques in which the part is produced by gradually growing material to the required shape. A tentative classification and nomenclature is proposed. It is shown that those new processes are ideally suited for CIM. The paper tries to compare the different processes and discuss their application and performances.
