Topics in Depth
The Theme of Antiviral Drugs in Microorganisms: Viruses
While the immune system does a lot to control virus infections, it obviously doesn't do everything, because we get sick. So, don't go giving it the "World's Greatest Immune System" mug yet. Fortunately, scientists have been developing drugs to stop virus infection for the last several decades, or centuries if you include vaccinations. Scientists have never had much faith in the immune system, which is why it has a complex—an MHC complex!
Ed. We at Shmoop would like to apologize for that last pun. The writer of that joke has been fired and is now sentenced to writing crossword puzzle questions for in-flight magazines.
When making a drug to stop a virus infection, there are several stages where most drug developers target, which include:
- Virus attachment to cell
- Virus replication (activity of polymerase)
- Virus maturation
When developing an antiviral drug, you need to keep in mind the fact that the drug might cause some damage to the host. Almost all drugs have some side effects that harm the host, but the tradeoff is they have some benefit. So, when developing an antiviral drug you look for a drug that meets the following criteria:
Dose inhibiting virus replication << Dose that is toxic to host
Since viruses use host enzymes for much of their replication cycle, there are only a few steps that can even be targeted by antiviral drugs. Coincidentally, those are the steps that we talked about previously. Unfortunately, many of these drugs have very toxic side effects, and only a handful of drugs have made it to the market. These include:
- Gancyclovir – anti-herpesvirus drug, targets thymidine kinase, which controls herpesvirus polymerase activity.
- AZT – a nucleoside reverse transcriptase inhibitors, blocks elongation of reverse transcription reaction with nucleotide analogs that don't have 3´ hydroxyl group.
- Nevirapine – part of the HIV non-nucleoside reverse transcriptase inhibitors, binds reverse transcriptase outside of the polymerase active site, and inhibits activity.
- Saquinavir – an HIV protease inhibitor, prevents maturation of the HIV particle.
- Ribavirin – a broad spectrum drug, meaning it targets many different types of viruses. Mutates RNA so that virus cannot replicate properly. Don't confuse it with riboflavin, the vitamin in Cocoa Puffs.
- Tamiflu – inhibits influenza hemagglutanin, the attachment/membrane fusion glycoprotein of influenza.
Antiviral drugs are generally developed using a process called structure-based drug design. What that means is that scientists generate a 3D structure of a viral enzyme, and the site of enzyme activity is identified. Once this occurs, computers model the active site and figure out what kinds of chemical compounds will fit into the active site to inhibit the activity of the virus enzyme. Think of it like finding a round hole, and going through a bunch of peg until you find a round one that fits in the hole. Sort of like finding the best wrench to stick into a machine to block it up.
But usually the computers find hundreds of chemicals that fit into the active site of the enzyme. So, the next process is optimizing the drug, which is based upon the following criteria:
- Is it easy to make chemically?
- Is it cheap to make?
- Does it have an optimal inhibitory/toxic dose ratio?
- Can it easily enter cells/the human body?
All of these factors are important in determining the efficacy of a drug as being an anti-viral. However, the problem with antivirals unlike vaccines or host immunity is that antivirals are highly specific, and viruses can easily mutate so that they can get around the specificity of the antiviral. This is why many antivirals, particularly against HIV have to be used in combination for optimum effect. A virus could become resistant to a reverse transcriptase inhibitor, or a protease, but not to both at the same time. And even if the virus manages to be resistant against both, it is unlikely that they'll be resistant to both as well as an anti-HIV membrane fusion drug. This combination of therapy in HIV is called HAART (Highly Active AntiRetroviral Therapy).
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