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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: derekb.lowe@gmail.com Twitter: Dereklowe

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May 21, 2012

A New Way to Kill Amoebas, From An Old Drug

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Posted by Derek

Here's a good example of phenotypic screening coming through with something interesting and worthwhile: they screened against Entamoeba histolytica, the protozooan that causes amoebic dysentery and kills tens of thousands of people every year. (Press coverage here).

It wasn't easy. The organism is an anaerobe, which is a bad fit for most robotic equipment, and engineering a decent readout for the assay wasn't straightforward, either. They did have a good positive control, though - the nitroimidazole drug metronidazole, which is the only agent approved currently against the parasite (and to which it's becoming resistant). A screen of nearly a thousand known drugs and bioactive compounds showed eleven hits, of which one (auranofin) was much more active than metronidazole itself.

Auranofin's an old arthritis drug. It's a believable result, because the compound has also been shown to have activity against trypanosomes, Leishmania parasites, and Plasmodium malaria parasites. This broad-spectrum activity makes some sense when you realize that the drug's main function is to serve as a delivery vehicle for elemental gold, whose activity in arthritis is well-documented but largely unexplained. (That activity is also the basis for persistent theories that arthritis may have an infectious-disease component).

The target in this case may well be arsenite-inducible RNA-associated protein (AIRAP), which was strongly induced by drug treatment. The paper notes that arsenite and auranofin are both known inhibitors of thioredoxin reductase, which strongly suggests that this is the mechanistic target here. The organism's anaerobic lifestyle fits in with that; this enzyme would presumably be its main (perhaps only) path for scavenging reactive oxygen species. It has a number of important cysteine residues, which are very plausible candidates for binding to a metal like gold. And sure enough, auranofin (and two analogs) are potent inhibitors of purified form of the amoeba enzyme.

The paper takes the story all the way to animal models, where auranofin completely outperforms metronidazole. The FDA has now given it orphan-drug status for amebiasis, and the way appears clear for a completely new therapeutic option in this disease. Congratulations to all involved; this is excellent work.

Comments (10) + TrackBacks (0) | Category: Academia (vs. Industry) | Drug Assays | Drug Development | Infectious Diseases


COMMENTS

1. microbiologist on May 21, 2012 5:58 PM writes...

Very cool

Permalink to Comment

2. anonymous on May 21, 2012 6:22 PM writes...

Is the "reaction" between the gold ion of auranofin and protein cysteines "merely" a thiol ligand exchange??? If not, how does it take place? Would also think this molecule is a source of sulphide (S dianion)?

Permalink to Comment

3. A Nonny Mouse on May 22, 2012 3:16 AM writes...

As an aside, I was involved with the company that bought the redundant plant in Spain where this was being made.

They found that the "yield" from the process was stated as much lower than in actuality and that less of the gold dust was being put into the reaction than was required- the rest being "lost" into someone's bank account.

They also found that there were enough light bulbs in the plant to keep it going for about 20 years; these too were being used as an addition source of income for employees.

Permalink to Comment

4. processchemist on May 22, 2012 4:02 AM writes...

@2

I know nothing about the metabolism of 2-glycothiols, but chemically speaking the sulphur in position 2 is a fairly good nuclophile and a poor leaving group. Like other thiols, is prone to easy oxidation. Probably the metastability of gold I has something to do with the MOA.

Permalink to Comment

5. Morten G on May 22, 2012 7:00 AM writes...

Recently I stumbled over this paper that says miltefosine (a drug against Leishmania) is effective in treating acanthamoebiasis, a rather rare amoebal disease:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2630722/?tool=pubmed
"Abstract
We report on an HIV-negative but immunocompromised patient with disseminated acanthamoebiasis, granulomatous amoebic encephalitis, and underlying miliary tuberculosis and tuberculous meningitis. The patient responded favorably to treatment with miltefosine, an alkylphosphocholine. The patient remained well with no signs of infection 2 years after treatment cessation."

The paper reads a bit like an episode of House =] but with actual medicine. They go straight from an in vitro result in some paper to clinical use.

Permalink to Comment

6. Morten G on May 22, 2012 7:05 AM writes...

PS Considering drugs like the -fosine 's and Victoza (liraglutide) maybe it's time for a post on long alkyl chains in drugs?

Permalink to Comment

7. Captain Falcon on May 22, 2012 10:04 AM writes...

Can a medicine based on gold be cheap enough to be used in the third world? And is there enough gold on the planet to make enough drug (or will we all have to smelt our wedding rings).

I like how you can't teach an old drug new tricks, but it turns out that many old drugs actually already know new tricks; we never asked them to do 'em.

Permalink to Comment

8. Matt on May 22, 2012 10:53 AM writes...

The upper range of human dosage for auranofin (in arthritis, at least) seems to be about 6 mg per day. That represents about 1.7 mg of gold. Higher dosages are avoided because of side effects (GI upset). Treatment with metronidazole seems to currently run for 5 to 10 days. If auranofin were given for 10 days that would be up to 17 mg of gold consumed during a course of treatment, or up to 89 cents for the gold at current spot prices for a course of treatment. Based on gold content alone it does look like this drug would still be cost-effective even in impoverished regions.

Permalink to Comment

9. Jonathan on May 22, 2012 5:47 PM writes...

A good example where the competitive edge of phenotypic screening, oft blunted by the relative lack of diversity in HTS libraries (whether vendor-produced or drugs), can be sharpened by a sophisticated assay others are less likely to be competing with.

Permalink to Comment

10. anonymous on May 23, 2012 6:22 AM writes...

Come on all you clever readers and mechanism gurus....can't we get an answer for the questions asked by #2????

Permalink to Comment

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