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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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February 26, 2002

New Drugs for HIV

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Posted by Derek

Megan McArdle points out the recent news (which has shown up in Tuesday's NY Times and other outlets as well) about new HIV treatments with possibly fewer side effects. She asks if the same technique can be applied to other diseases, and I thought for the benefit of the non-pharma audience that I'd go into some detail on that.

Actually, there's no particular new technique involved - just good ol' drug development. These compounds work by different mechanism than the stuff we've had so far. Here's a (fairly) quick explanation, centering around one of the therapies highlighted in the press reports, the one from Schering-Plough.

The specific target of that compound is a protein called CCR5, which sits straddling the outer membrane of some types of cells. Part on the outside, part loops to the inside. It's one of a huge class of proteins called receptors, whose lot in life is to latch onto specific other molecules if and when they come by. When they do, that binding event sends a signal into the cell, and these signals can be tied into just about every cell process you can think of. This is one general way that you can enable some molecule floating outside the cells to set off changes inside them.

The subject, like most molecular pharmacology, rapidly reveals its career-worthy godawfulness on closer inspection. All those things in the above paragraph vary hugely and interrelatedly. To give you an idea, various receptors are a key step in the actions of things as important (and as unrelated) as insulin, cocaine, growth hormone, and caffeine. They're still counting up how many different receptors there are from the human gene sequences, but it's probably going to be in the low thousands when the dust settles.

In the mid-1990s, studies on patients who appeared more naturally resistant to HIV showed that they had a mutated form of CCR5. It turned out that the receptor is one of the things that the virus uses to get into blood cells and infect them, but the mutated form didn't let HIV bind to it very well. That immediately led to the idea of blocking a normal patient's CCR5 with some small drug molecule - if the receptor were stopped up with that, maybe HIV wouldn't be able to bind to it, either.

This receptor-blocking idea is a favorite in drug research. It's usually a lot easier to gum up a receptor than it is to mimic the specific thing that turns it on. That's why everyone jumped on this idea so quickly. So far, it seems to work, and congratulations to the Schering-Plough team for it. Although I haven't talked to them about it - not that they'd tell me anything, either - I know several of the chemists who worked on this project. They and their biology colleagues deserve the success.

But will this lead to a marketed HIV drug? Good question. It's obviously made it through the animal toxicity testing I spoke about the other day, because the compound has shown efficacy in humans. Those are both big steps. Now come more studies, with more patients, to make the case to the FDA. It's not an early-stage drug any more, and the odds are fairly good that it'll make it, but there are still several places where it could banana-peel and slip off the tightrope.

If it does, will it have fewer side effects than the protease inhibitor cocktails? Another good question. Right now the only thing you can be sure of is that the side effects will be different. All drugs, every single one of 'em, have side effects. Some are major, some are minor, and some are minor only relative to the disease that's being treated. Since this doesn't work on HIV protease, it presumably will avoid the problems of those drugs, which is good news. But there could always be others out there waiting.

There could mechanism-based tox, for example. We really won't know until larger, longer trials are conducted what might happen when you block CCR5 for an extended period, what happens when you block it while you're taking other drugs at the same time, or if there's some subset of the patient population that will react unusually.

Or there could be non-mechanism-based tox, which is what happened with the protease inhibitors: keep in mind that (when the research began) no one expected the body-fat remodeling and the other side effects of that class. Those seem to have nothing to do with blocking HIV protease, and arguments rage as we speak about what causes them. Is there some other protease that you can't avoid hitting when you go after the one in HIV? Could be. Is there some totally unrelated thing with (by sheer bad luck) a similar-looking binding site, so that most anything that binds HIV protease will hit it, too? Can't rule it out.

None of these arguments are specific to the HIV therapy field, of course. Investigative drugs go down the tubes all the time for just these sorts of reasons. And sometimes even the large trials aren't enough to catch bad side effects that occur at very low frequency, and you get the serious bad news after the stuff has gone to market. That seems to be what happened with the diabetes drug Rezulin (troglitazone,) and it's not the only example. When that happens, so many lawsuits start flying that it looks like it's snowing.

Am I a gloomy researcher or what? Nah, just realistic. I'm actually fairly perky most of the time, so I'll end on an optimistic note:. What we have now are some new ways to treat a terrible disease. The more routes of attack we have, the better. Along the way, we're learning a lot that can help out in other fields as well. The great thing about drug discovery, about science in general, is that nothing's ever really in vain, and no good work is ever really wasted. It all adds up, and keeps adding up. And what we're building, I truly believe, is the greatest work of the human race.

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