Inching Toward An Obesity Drug Target?

ResearchBlogging.orgAs the race to discover a new obesity drug continues, it's important to consider what makes a good obesity drug target. Before you bother putting a team of medicinal chemists on the job of making a small molecule that could be the next big diet pill, what do you need to know about the target you're chasing? A new paper in Nature (DOI: 10.1038/nature08921) raises that question this week. A research team led by Jijie Chai of the National Institute of Biological Sciences and Tsinghua University, both in China, has determined the molecular structure of FTO (fat mass and obesity-associated protein). This protein, as the name suggests, has been strongly linked to obesity. Before this paper, scientists knew what kind of protein FTO was- an enzyme that removes methyl groups from DNA and RNA, that prefers to clip methyls away from single stranded substrates. But they didn't have the molecular specifics. Now, with the structure solved, it paves the way for development of small molecules that can block or otherwise alter FTO's activity. But don't assume we've now got an easy path to new obesity drugs. There's more to the story. I touched on some of it here.
FTO isn’t ready to be declared a prime obesity drug target, cautions Claude Bouchard, who specializes in the genetics of obesity at the Pennington Biomedical Research Center, in Baton Rouge, La. Geneticists cannot rule out that the gene for FTO is a surrogate for or is working with a nearby gene to affect obesity risk, he says. The natural substrates for FTO remain to be identified, and it may be tough to design drugs that selectively block demethylation of obesity-relevant ones, he adds.
FTO is strongly linked to obesity in several studies. However, the gene for FTO is very close to another gene called FTM, Bouchard says. "They are almost universally co-expressed in animal models- these genes move in tandem," he says. So it's not clear from genetic tests so far whether FTO is the culprit, and if it is, whether it's working alone. The picture gets more interesting when you find out what FTM does. It's involved in the biology of cilia, the little hairlike structures that protrude from the surfaces of some cells. What's fascinating about that is that at least one genetic disorder of cilia, Bardet-Biedl syndrome, is characterized by obesity, Bouchard says. So, what's going on? We may need more genetic tests to figure this out. Or we could still use small molecule inhibitors of FTO activity to probe whether turning it off is enough to stop obesity. It would've been nice for a story like this one to give you that fuller context. A second concern that I didn't bring up in the story linked above was statistical: though the link between FTO and obesity may be strong, FTO still accounts for a very small risk of becoming obese, Bouchard says. It's not certain that the payoff of developing a drug to target it will be as significant as that for other targets. Bouchard also brought up the question of selectivity.
The natural substrates for FTO remain to be identified, and it may be tough to design drugs that selectively block demethylation of obesity-relevant ones, he adds.
I posed this question to Chai in an email, and here is what he wrote back.
Inhibitors usually block the activity of an enzyme by targeting its active site that is responsible for binding of all substrates. So unless striking differences exist among the substrates of a given enzyme (which generally is not the case), it would be tough, if not impossible, to design inhibitors that can block the binding of a specific substrate. But this does not seem to be a big problem for inhibitor to become drugs, becasue(sic) a malfunctional enzyme in patients is often overactive to all its substrates and thus renders people susceptible to some diseases.
Most of the drugs in late-stage clinical trials for obesity reduce food intake by affecting the central nervous system, changing perceptions of hunger or fullness. A few act at the gut, preventing nutrients from being absorbed. If FTO does turn out to be a bona fide drug target, it'll be exciting to see a new mechanism of action, blocking nucleic acid methylation, added to the obesity area. But we don't know that for sure yet. Han, Z., Niu, T., Chang, J., Lei, X., Zhao, M., Wang, Q., Cheng, W., Wang, J., Feng, Y., & Chai, J. (2010). Crystal structure of the FTO protein reveals basis for its substrate specificity Nature DOI: 10.1038/nature08921

Author: Carmen Drahl

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