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Fred11   Sep-21-00, 05:35 PM (CST)
"Rattus......"
Rattus,

I had around 50 hours Bio & Chem in school, though it has been a while. Acyclovir, where in the cellular activity does it attack the virus?

Just wondering and thanks,

Fred

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 Table of contents

Simplified Mechanism, Rattus, Sep-21-00, (1)
RE: Simplified Mechanism, mzztree, Sep-22-00, (2)
RE: Simplified Mechanism, Fred11, Sep-22-00, (3)
RE: Simplified Mechanism, Rattus, Sep-22-00, (4)

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Rattus Click to EMail RattusClick to check IP address of the poster Sep-21-00, 09:18 PM (CST)
1. "Simplified Mechanism"
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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mzztree   Sep-22-00, 05:28 AM (CST)
2. "RE: Simplified Mechanism"
Rattus, that was great. Well explained and easily understood. Thanks for the info, and the tidbit on the Nobel prize.

MzzTree

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Fred11   Sep-22-00, 07:40 AM (CST)
3. "RE: Simplified Mechanism"
Rattus,

Thanks for the explanation!!!!!!!! It reminded me of my school days, long, long ago.

OT: Had Bio Prof. that was an assistant with Watson and Crick. The man is bright!!!

Also, one time I got so sick of the public. I researched lighting bugs. In Saint Louis there is an outfit called Alpha industries. They buy lighting bugs from 4H and Scout Troops. I wondered why? Turns out the enzyme that causes them to blink, Luthernamise (spelling?) is used in cancer research. Cells with healthy ATP give off a given hue, as potentially cancerous cells reflect something different.

Plus, don't know how it was correlated, but the enzyme is instantly disorientating to sharks. Another words a good market for the enzyme.

I was just planning to build a place to raise lighting bugs, when someone synthesized the enyzme. I was heart broke.

Thanks again for the explanation!!

Fred

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Rattus   Sep-22-00, 01:13 PM (CST)
4. "RE: Simplified Mechanism"
Hey Fred:

Its actually called luciferase and when mixed with luciferol, gives off light as a by-product of the reaction.

The advantage of using this assay is that if you try to deliver a gene say for cystic fibrosis and you want to see if the protein product of that gene is being made, you tag the DNA of luciferase to the end of the CF gene. Then you use whatever vehicle you want (ie virus, direct IV injection) to get the gene into the tissues. Then you sample the tissue and litterally cuisinart in into to fine bits. Take off the supernatant fluid from the mash and put in in a test tube. Insert the tube into a luminometer (a machine which measures the intensity of light against a standard curve) and add a known amount of luciferol. If the reading is above background, that implies that your DNA was taken-up by the cells and that the desired protein was produced.

In other words, it is a very useful surrogate marker for gene expression.

There was a beautiful tobacco plant that had the luciferase gene engineered into its cells. The cells of the plant then passed the gene on to all other growing cells. When the plant was mature, the scientist then watered the plant with dilute luciferol and the whole plant lit-up like a fire-fly. You probably can find this picture on the WEB as it is in all the basic biology textbooks.

Best Regards,

Rattus

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