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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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April 1, 2010

Good News Versus Sleeping Sickness

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Posted by Derek

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.

Comments (22) + TrackBacks (0) | Category: Infectious Diseases


1. curious on April 1, 2010 10:57 AM writes...

Is it possible to deliver drugs in a binary form, i.e. two components that can penetrate the blood-brain barrier that recombine once across?

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2. anon the II on April 1, 2010 12:16 PM writes...

Answer to #1


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3. David on April 1, 2010 1:05 PM writes...

And what about intrathecal administration? Is the CNS disease amenable to treatment via a drug in the cerebral spinal fluid? If so, is the lead compound safe in the CNS? Does it re-distribute to the CNS around the brain? Can it be formulated as an intrathecal preparation? Is it at all economically feasible to treat as daily intrathecal administration? (probably not)

Just wondering.

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4. Anonymous on April 1, 2010 1:20 PM writes...

Pardon my callousness (or misinformation if that is the case), but isn't the real problem the fact that no pharma company will develop these compounds because they can't make any money off of third world countries?

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5. sad on April 1, 2010 2:31 PM writes...

@ #4: Sadly, I think you are right.

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6. darwin on April 1, 2010 2:46 PM writes...

But if the trypanosome target holds true for t. cruzi as well, it might get interesting enough to develop and you wouldn't necessarily have to penetrate CNS for clinical POC.

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7. alig on April 1, 2010 2:57 PM writes...

If we just expand healthcare reform to cover those people in third world countries, then maybe pharma companies will make drugs to treat third world diseases.

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8. David P on April 1, 2010 3:19 PM writes...

@4: That used to be true but recently a number of groups have appeared that seek to treat neglected diseases, with help from foundations like the Gates Foundation. Two spring to mind, one is specifically looking at malaria (malaria foundation), another more general (drug for neglected diseases initiative).

Drug companies have put up libraries for screening and helped out generally. Not a big money spinner for them of course, but they are doing something to help.

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9. Jose on April 1, 2010 3:29 PM writes...

"...but they are doing something to help."

Not exactly. They are simply providing the structures (no screening quantities) from combi chem garbage libraries and then getting max PR exposure to satisfy their CSR goals.

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10. anon on April 1, 2010 4:04 PM writes...

NMT. Hmmm. I remember back 20 years or so; Monsanto and others were looking at NMT for HIV. Much of the viral envelope is myristic acid. I don't think the efficacy was high for that indication.

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11. sgcox on April 1, 2010 4:45 PM writes...

This is a very good and thorough piece of science work.
Unfortunately, its real life impact is likely to be quite low. Next to negligible.
The reason is the awful political situation in the affected areas which preclude the proper and timely diagnosis and administration of the drug. It should be done at first clear and obvious infection symptoms, not when CNS damage put the person to the road to death. Until some semblance of stable health care system is in the place, all these wonder drugs will not reach patients at the time of need. Blaming Big Pharma for this situation is beyond the joke.

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12. ron richardson on April 1, 2010 7:14 PM writes...

Is there oral bioavailability? that seems like it should be a prerequisite for this kind of drug to be distributable...

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13. gippgig on April 1, 2010 9:12 PM writes...

#4: Look at the Institute for OneWorld Health (

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14. Eric Jablow on April 2, 2010 12:23 AM writes...

Lead compounds? Is that even possible? Are there any Pb-based drugs, or am I reading that badly wrong?

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15. gippgig on April 2, 2010 3:13 AM writes...

That's "lead" as in "in the lead", not "lead" as in the chemical element. You've been misled.

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16. Richard Mead on April 2, 2010 5:26 AM writes...

@8: well said, the Dundee group has been very well supported by the Wellcome Trust to set up drug discovery activities for neglected diseases. They have recruited some really good people from Pharma and its great to see them having an impact.

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17. David P on April 2, 2010 8:51 AM writes...

"Not exactly. They are simply providing the structures (no screening quantities) from combi chem garbage libraries and then getting max PR exposure to satisfy their CSR goals."

It is easy to be cynical about Big Pharma, but in this case, I think you might reconsider.

They are actually collaborating with these foundations and initiatives.

GSK's "open Lab" story:

I have also seen a presentation from Drug for Neglected Diseases initiative, they also have pharma collaborators.

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18. anonymous on April 2, 2010 9:40 AM writes...

I spoke with a professor who used to have a collaboration with the Institute for One World Health and he said they were incredibly shady. Apparently their business model was to start collaborations with academic groups and then try to steal the best compounds and patent them as their own. Several groups complained, enough that the Gates foundation razed the entirety of upper management and replaced them.

Hopefully they're back on track, the work they're doing is noble in my opinion.

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19. Jose on April 3, 2010 2:16 PM writes...

David P- from your article: "According to the AP, GSK will let other scientists try to develop malaria drugs – free from royalties or other payments to GSK – from that library of compounds."

This is exactly my point. This (and some funding) is essentially evidence of my point. "Here are some [lousy] HTS hits- good luck!" An HTS screen is so laughable far away from a useful drug in terms of money and manpower, it is just a PR ploy and nothing else. Academic groups (at Emory or elsewhere) can't even begin to tackle it; Derek has some nice posts on academic DD.

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20. Guzzo on April 3, 2010 3:25 PM writes...

Hmm.. I wonder if it would work for Chagas Disease too? If no pharma finds a profit potential in it, maybe it could be presented to Bill Gates?

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21. Anonymous on April 5, 2010 5:59 AM writes...

"An HTS screen is so laughable far away from a useful drug in terms of money and manpower, it is just a PR ploy and nothing else. Academic groups (at Emory or elsewhere) can't even begin to tackle it; Derek has some nice posts on academic DD."

Actually there is a track record for inhibiting NMT in the fungal area starting from HTS hits - Pfizer ran a programme for which there are a couple of ACS meeting abstracts but no papers. NMT has been kicking around as a great target in the anti-infectives area for some time as the enzyme is quite variable across lots of interesting targets so selectivity against the human enzymes is pretty achievable.

Pharma companies giving away HTS data is a really big deal as far as I can see - the most daunting aspect of setting up an academic drug discovery group is the shortage of viable lead matter. While it is trendy to talk down the impact of libraries I've seen many viable lead series from multiple programmes derived by HTS screening efforts. Recent pharma failures have been more down to target selection than finding viable leads.

And while I would happily shoot most academic medicinal chemists confident that I would be having no effect on the progress of science, the Dundee group is a little bit different. There are some battle hardened veterans there who actually do know what they are doing. Let's hope that their funding allows them to concentrate on what really needs doing, rather than being publication focused.

Still, I'm not sure I'd want to have to try and drag that sulfonamide into the CNS. Let's hope it's not necessary. And they've got some work to do on selectivity yet.

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22. sepisp on April 22, 2010 8:36 AM writes...

Why did I get the feeling that most posters didn't read the blog entry or the paper? The lead worked in vivo, it's not just a structure from HTS. There are several other reasons why this isn't irrelevant. Many of the current drugs for tropical diseases like this are toxic and often ineffective. Many tropical countries are actually undergoing economic growth and development, so the idea that they'll stay poor forever is short-sighted. And you can't neglect the rich in those countries; there are more rich people in India than there are people in many European countries. Furthermore, climate change will cause the spreading of tropical diseases further north.

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