The antiviral virus
These are some of the drugs used in the therapy against HIV.
They all work. Sort of.
However, they have dreadful toxicity and need to be taken in multi-drugs regimens, due to resistance and, in a nutshell, lack of power.
Some of them are rather amazing: efavirenz, for instance, and all the other non-nucleotide inhibitors have lovely structures.
The idea behind protease inhibitors is, in my opinion, brilliant (although they cause nasty adverse effects).
To sum up, these molecules are rather useful, but, somehow, they are...banal.
I mean, they don't have any feature which might eventually distinguish them among other antiviral. Nothing special which may make you fall in love with them, as I did with Imatinib.
And, besides, they were all designed in a rather predictable way: here is the virus, here are its enzymes...well, you know the rest, don't you?
If I studied medicine, I would probably like to become a microbiologist, in the end. And if I were a microbiologist (but, maybe, even as a pharmacologist can: who knows?), no doubt I'd focus on what is likely to be the least-known virus: HGV (hepatitis G virus).
You certainly heard of HBV and HCV, but I bet you never came across type G virus. Actually, this is no surprise: this RNA flavivirus is a relatively new (its discovery dates back to 1995) and has rather unusual characteristics.
In fact, it doesn't even cause a real disease. And it's not even hepatotropic, since its replication takes place in mononuclear cells.
Now, at this point, you might be thinking: "Why, the Hell, should anyone waste time on such a ridiculous virus, of which you can't even find a picture (or drawing) on the net?!"
Well, you would be wrong, because this could become the most important virus, ever! In particular, for what concerns HIV.
That's why the only, evident effect of HGV infection is dramatic reduction in the rate of replication of HIV. Not bad for a viral infection, eh?
To sum up, one of the least-known viruses seems to be an astonishing weapon against the most important of the viruses.
Not only did in vitro studies prove an inhibition in the replication of HIV in blood mononuclear cells, but similar findings resulted from experiments on HIV-infected patients.
Imagine this: you, mighty graduate student, choose a rubbish university, your PhD research project focuses on a virus no one cares about or even heard of and you end up finding a biochemical pathway (or some protein produced by HGV), which explains how this hepatovirus could inhibit the replication of HIV and leads to the development of a new, revolutionary class of drugs which can wipe out HIV infections and whose sole drawback is, say, somnolence!
Honestly, I can't think of anything better.
I mean, they don't have any feature which might eventually distinguish them among other antiviral. Nothing special which may make you fall in love with them, as I did with Imatinib.
Well Albert, you need to keep in mind how those drugs were discovered. Researches in the late 80ies simply took the nastiest drugs they could find and screened them for efficiency against HIV. No wonder they don't have subtle sophisticated and well-explored mechanism. Nevertheless, as you said, they work in combination with nasty side-effect. But since AIDS patients don't have long life-expectancy anyway, it's rather easy pushing such drugs through clinical trials quite quickly.
In vitro studies suggest that GBV-C inhibits HIV replication and alters cytokine, chemokine and chemokine receptor expression. Thus, GBV-C may be a major factor influencing the natural history of HIV disease.
I wonder what ramifications this has on the immune system in healthy individuals.
Interesting post!
As someone who has been in the area for a long time I can come to the defense of antiviral med chem by highlighting some interesting developments in the field with some potential applications to other areas of med chem. For example, Arun Ghosh's work in the design of HIV protease inhibitors which are active against resistant viruses is very interesting. It involves the fine-tuning of a hydogen bond to a conserved amino acid in the substrate binding domain of the enzyme. With respect to NRTI's, there has been some recent developments in understanding the mechanisms tht HIV uses to effect resistance to the Thymidine based agents.
After the introduction of HAART, it became apparent that the side-effects associated with therapy were contributing to patient non-compliance that eventually results in the development of resistance when pateints miss their doses. Given that most anti-HIV drugs are high dose (>300 mg BID) and are given for life, even minor issues with toxicity and side-effects can have a dramatic effect over the long term. Therefore, there is a high premium on finding drugs with reduced side effects that can be given less frequently. There is currently very little tolerance for side-effects and this makes finding new drugs very challenging.
Regarding GBV-C/HGV, the NS5A-protein has been suggested as the anti-HIV agent.