Hi Fred:Acyclovir acts by mimicking a cellular DNA constituent, guanine. That is the "G" in the AT-CG of DNA. Although it is structurally similar to "G" it is missing it's tail-- a hydroxyl "cyclic" ring--thus it is "acyclic". That hydroxyl tail in normal guanine is where the next building block of DNA chemically binds. Thus as a DNA stand lengthens, the hydroxyl tails all link.
Before guanine or acyclovir is active is must be phosphorylated 3 times. This occurs in the cell. Normally the human receptors on the inner membrane of the cell (thymidine kinase, "TK") are sophisticated enough to reject acyclovir as a guanine mimicker (although at high concentrations it can be forced into uninfected cells). The virus, after millions of years of development figured out the best way to ensure that it gets priority over the DNA building blocks is to make its own TK. The fatal flaw is that it is very unsophisticated in that it cannot differentiate between real guanine and
fake guanine. Thus, acyclovir readily gets phosphorylated (i.e.
activated) by the viral TK.
The process then continues where human enzymes add the remaining 2 phosphorous molecules and then the viral DNA polymerase picks it up as fully activated, real guanine tri-phosphate and adds it to the growing DNA chain. However, wherever it is added (ie the beginning, middle or end of the chain) that's it! Nothing more can be added because the next DNA building block has no hydroxyl group to latch on to. Thus the assembly of that virus is permanently terminated.
This leads to the logical conclusion that acyclovir has no effect on already produced virus. But if it escapes the neuron intact, it's attempts to later replicate itself in epidermal cells will be limited by therapeutic levels of acyclovir.
Of note viral TK binds acyclovir 200 times more efficiently than human TK and does it at a rate 30 to 120 times faster than human TK. Thus uninfected cells rarely accumulate acyclovir.
Acyclovir is a prototypical masterpiece of rational drug design and the woman who invented it did win the Nobel Prize for her work on the drug.
Resistance is theoretically not an issue because there is no change in the make-up of the latent DNA. Replication errors will surely produce resistant virus from time to time, but you will not be re-infected with this resistant strain. There is no data available regarding the obvious question of selecting for resistant virus and then passing it on. This either doesn't occur or does so with such rarity that it can't be reliably studied in humans.
Another weakness of the virus is that when it exits a cell's nucleus or outer membrane, it takes a piece with it. These membranes are essentially fat and the virus requires them for infection/immune evasion. Since it is just oil, basic soap or alcohol will readily dissolve the membrane making it not infectious.
It's hard without diagrams, but I hope this makes sense. I'll look for a link or pharmacology review for you.
Best Regards,
Rattus
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Simplified Mechanism,
Rattus, Sep-21-00, (1)
RE: Simplified Mechanism,
mzztree, Sep-22-00, (2)
