Production Of New Virus Particles Research Articles

Neplanocin A. A potent inhibitor of S-adenosylhomocysteine hydrolase and of vaccinia virus multiplication in mouse L929 cells.

Neplanocin A, a novel cyclopentenyl analog of adenosine, is a naturally occurring antibiotic which exhibits significant antitumor activity against L1210 leukemia in mice (Yaginuma, S., Muto, N., Tsujino, M., Sudate, Y., Hayashi, M., and Otani, M. (1981) J. Antibiot. 34, 359-366). In the present study we demonstrate that neplanocin A is also a potent inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase (EC 3.3.1.1) having a Ki of 8.39 nM for the purified bovine liver enzyme. Analysis of the apparent irreversible inactivation of AdoHcy hydrolase by neplanocin A indicates that the drug is a tight binding inhibitor, exhibiting a stoichiometry of one molecule of inhibitor to one molecule (tetramer) of enzyme. In addition, we show that neplanocin A is a potent inhibitor of vaccinia virus (WR) multiplication in monolayer cultures of mouse L-cells. Concentrations of the drug as low as 0.5 and 1.0 microM in the culture medium produce 84 and 95% inhibition of plaque formation, respectively, while exhibiting little toxicity to the host cells. The inhibition of virus multiplication by neplanocin A coincides with a rapid inhibition of AdoHcy hydrolase activity in the infected cells and a subsequent 10-fold increase in the intracellular AdoHcy/S-adenosylmethionine ratio. These findings suggest that the antiviral actions of this compound may be related to an inhibition of S-adenosylmethionine-dependent macromolecular methylation reactions which are essential to the production of new virus particles (e.g. viral messenger RNA).

Cancer--a theory.

WOLLMAN, 1 of Paris, commenting on his experience in bacterial genetics, believes that there is a group of bacterial agents which may well be models for the type of viruses that could be carcinogenic. These agents are infective under some conditions and mutagenic under others. Lysogenic bacteria can produce viruses even without coming into contact with outside viruses. In their infective state the produced viruses, known as temperate bacteriophages, are able to infect sensitive bacteria and then to foster production of new virus particles in accord with traditional virus mechanism. But the temperate bacteriophages also have a noninfective prophage state. Prophages, occupying specific sites on the chromosomes, are integrated with the genetic apparatus of the bacteria so that, in effect, they can produce mutations. Perhaps, the French investigator suggests, this situation is analogous to the mode of action of carcinogenic viruses, capable in one form of causing disease by