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April 1, 2010
Good News Versus Sleeping Sickness
Nature has a very encouraging paper out today on some potential treatments for trypanosomiasis (sleeping sickness). The mechanism is protein N-myristoylation (catalyzed by an enzyme abbreviated as NMT) which is a process that's important for membrane targeting and trafficking. NMT has been shown to be essential for trypanosome survival by siRNA experiments, so it's a pretty well-validated target.
And now there's some chemical evidence for that idea. This groups screened a compound library, found some micromolar-level hits, and optimized these through good old-fashioned medicinal chemistry down to nanomolar-level compounds. The compounds aren't that bad - they're all pyrazole sulfonamides, a bit bulky and aromatic, but everyone who's done med-chem has seen a lot uglier compounds than these. Here's an X-ray structure of the lead bound to the target enzyme.
And more to the point, that lead compound actually works. In two models of sleeping sickness infection in rats, it cured every single animal in the test group. There's a lot of evidence presented that the compound is working on-target; it certainly convinces me. It's also good news that it doesn't seem to be showing toxicity, because human cells use NMT of their own. All in all, this compound is an excellent start, and may well be a drug candidate all by itself.
But if it is, it's only going to be useful in the earlier stages of the infection. The nastiest part of the disease is when the parasites make it into the central nervous system, but these compounds don't seem to penetrate into the brain. The paper mentions that further optimization is underway to try to address this, and I wish them good luck, and quickly. And I hope that this report stimulates other people to look through their own compound collections for NMT inhibitors that might do the same thing.
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