Chemotherapy III: Antiviral Drugs

Now we're going to move onto another target: viruses!

Understand basic viral structure, biology, life cycle and pathogenicity.

Viruses are essentially just packages of DNA or RNA. They don't have organelles or anything like that to sustain themselves: instead they have to go into a cell and hijack the cell's machinery in order to replicate and thrive. (This is why designing antiviral drugs can be hard: you want to stop the virus from replicating, but you don't want to stop normal DNA replication from occurring either.)

Viruses have a nucleic acid core, surrounded by a coat, or capsid. This capsid is made up of proteins called capsomeres. The nucleic acid and capsid together are collectively known as a nucleocapsid. The capsomeres are of importance as their binding to receptors on the cell allows the virus to be taken up by the cell.

Here's what happens, in a little more detail than in the first paragraph: the capsomere proteins bind to receptors on the cell, the virus gets taken up and sheds its capsid, and viral DNA or RNA is produced. This viral DNA/RNA goes on to code the structural, enzymatic and regulatory proteins that the virus needs. These include capsomeres, allowing viral proteins to be packaged up and exocytosed from the cell. This allows the virus to go on and infect more cells.

Understand the mechanistic basis for the use of acyclovir as the first effective antiviral drug.

Acyclovir, as its name suggests, does not have a ring (a = without, cyclo = ring). Acyclovir is actually similar to deoxyguanosine (one of the bases of DNA), but it is missing that fundamental cyclic ring structure. This also means that it's missing a 3'-OH, so DNA synthesis cannot continue if acyclovir is added instead of deoxyguanosine. In this way, acyclovir acts as a purine analogue inhibitor- it's a purine analogue (i.e. it looks like a purine, in this case guanosine), and by doing so, it inhibits viral DNA replication. This is because it either competitively inhibits DNA polymerase, or as alluded to a couple of sentences ago, it can bind in place of a guanosine and prevent further synthesis from occurring.

Acyclovir can't do this on its own, however. As mentioned in a previous post, nucleosides lacking phosphate groups aren't added onto a chain- instead, nucleoside triphosphates are required. Hence, acyclovir is actually a prodrug that requires some more processing to be able to do its job. Each processing step simply involves addition of a phosphate group. Firstly, this is done by viral thymidine kinase (a kinase produced by the virus, so essentially the virus is being complicit in its own murder!). The second and third phosphorylations are simply carried out by kinases normally present in the cell.

Demonstrate a basic understanding of AIDS.

AIDS stands for Acquired Immune Deficiency Syndrome and is defined by a loss of CD4+ T-cells (important in our immune system). It comes about as a result of immune system damage from the Human Immunodeficiency Virus (HIV). The symptoms of HIV can be quite varied, as the weakened immune system lays down the foundation for opportunistic infections to occur. (Opportunistic infections are those that wouldn't normally hurt a healthy person, but can be quite deadly in people without functional immune systems.)

HIV is an RNA retrovirus, which means that it has RNA as well as an enzyme called reverse transcriptase that can turn that RNA into DNA. It exists in two forms: HIV-1, which is more common, and HIV-2, which is less virulent. HIV can attach to its target cells through the interaction of HIV glycoproteins with surface receptors on a variety of cells, including T-lymphocytes expressing CD4 glycoprotein (i.e. those CD4+ T-cells that I referred to earlier).

The main factors to take into consideration when deciding to implement drug therapy are CD4+ T-lymphocyte numbers as well as HIV RNA copy number. CD4+ T-lymphocyte numbers decrease as the disease progresses. HIV RNA copy number, indicative of viral load, increases as the disease progresses.

Show appreciation for major drug classes used to treat HIV-infected patients.

The key targets for treating HIV include receptor binding (e.g. CCR5 receptor blockers), fusion, reverse transcriptase, integrase (inserts viral DNA into the host DNA) and proteases (which in this case can actually aid viral maturation- more on these later). Here I will be focusing on reverse transcriptase inhibitors and HIV Protease inhibitors.

First off, a quick look at reverse transcriptase inhibitors. These come in two classes: NRTIs (Nucleoside Reverse Transcriptase Inhibitors- they work by mimicking nucleosides, kinda like the purine analogue inhibitors I talked about earlier), and NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors- do not look like nucleosides). The NRTI class includes AZT (azidothymidine), which was the first anti-HIV drug.

HIV Protease is kinda unique. Remember how I said that viral DNA/RNA codes for coat proteins that help package up more virus and send it out of the cell? Well, HIV protease, weirdly enough, plays a role in the synthesis of the coat proteins. You see, HIV makes "polyproteins," which are essentially multiple proteins all mashed together. Proteases break them up into individual coat proteins. Drugs that target this pathway include saquinavir and atazanavir.

Usually, HIV patients are put on several drugs to manage their symptoms. HAART (Highly Active Antiretroviral Therapy) is the fancy name given to these cocktails of drugs. HAART usually consists of an NRTI, an NNRTI and a protease inhibitor. So far, this has been our most effective treatment against HIV.

Understand how drug resistance can limit the effectiveness of anti-HIV drugs

Unfortunately, unlike bacteria, HIV is also prone to building up resistance mechanisms. This is partly because HIV's reverse transcriptase has a low fidelity (i.e. very error-prone), so mutations can occur readily. Some of these mutations may confer resistance to a drug. There are now some drugs available against the most common mutant variants, but unfortunately these are still quite expensive.