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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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January 21, 2010

An Enzyme Inhibitor You Have Never, Ever, Considered

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Posted by Derek

I promise you that. Take a look at this abstract:

". . .an unappreciated physicochemical property of xenon has been that this gas also binds to the active site of a series of serine proteases. Because the active site of serine proteases is structurally conserved, we have hypothesized and investigated whether xenon may alter the catalytic efficiency of tissue-type plasminogen activator (tPA), a serine protease that is the only approved therapy for acute ischemic stroke today."

They go on to provide evidence that xenon is indeed a tPA inhibitor. And as it turns out, there's more evidence for xenon having a number of physiological effects, and enzyme inhibition has been proposed as one mechanism. Who knew?

Now, there's an SAR challenge. . .

Comments (19) + TrackBacks (0) | Category: Biological News


COMMENTS

1. Hap on January 21, 2010 12:13 PM writes...

How about radon? I'm sure that'll work.

"Dad's having a heart attack? What should we do?"

"Drag him downstairs to the basement and tell him to breathe deeply."

Permalink to Comment

2. Vader on January 21, 2010 12:17 PM writes...

In sufficient concentrations, radon is a powerful inhibitor of almost all enzymatic activity.

Breathe concentrated radon, and you'll be reduced to room temperature rather quickly.

Permalink to Comment

3. Hap on January 21, 2010 12:20 PM writes...

I take it the decay won't warm your body much?

Permalink to Comment

4. Jonathan on January 21, 2010 12:58 PM writes...

Seems like it would be a challenge to actually administer too. Gas-filled microcapsules perhaps?

Permalink to Comment

5. PharmaHeretic on January 21, 2010 1:30 PM writes...

Jonathan,

There you go..
_____________________________________________
Closed-circuit xenon delivery using a standard anesthesia workstation.
Rawat S, Dingley J.
Anesth Analg. 2010 Jan;110(1):101-9.

Permalink to Comment

6. Jackalope on January 21, 2010 1:33 PM writes...

The controlled administration of radon gas for therapeutic benefit has been achieved for some time outside of Butte, Montana.

http://www.radonmine.com/

The folks here are lovely and there are nice views of the Big Sky country when you emerge from underground.

Permalink to Comment

7. Boghog on January 21, 2010 1:39 PM writes...

The next frontier: From fragment to atom based drug discovery!

Permalink to Comment

8. Hap on January 21, 2010 1:42 PM writes...

I thinking I was more stupid than usual. Why would you want to inhibit tPA? Do hospitals use it for anesthesia (or anything else) that it would possibly be around to inhibit serine proteases and thus have unwanted effects?

Permalink to Comment

9. leftscienceawhileago on January 21, 2010 2:29 PM writes...

Just though it might be useful to mention a number of crystal structures have been solved with the help of cryofreezing xenon pressurized protein crystals. Xenon tends to find it's way into hydrophobic pockets, I'm guessing this is the underlying mechanism behind its use as a anesthetic.

Permalink to Comment

10. Wavefunction on January 21, 2010 3:08 PM writes...

For some reason Linus Pauling's theory about anesthetic gases working by forming clathrates comes to my mind.

Permalink to Comment

11. Paul on January 21, 2010 4:54 PM writes...

Hasn't there been work on using spin-polarized Xe129 for nuclear magnetic resonance imaging?

Permalink to Comment

12. Chemjobber on January 21, 2010 5:04 PM writes...

Boghog: LOL.

Permalink to Comment

13. Hap on January 21, 2010 6:59 PM writes...

I think Alexander Pines has done work with it - I saw a talk by him on it in grad school.

Permalink to Comment

14. chemist on January 21, 2010 7:49 PM writes...

#10: Linus Pauling's clathrates

I'm thinking Critical Volume Hypothesis. See the plot at the wikipedia entry: Xe, Kr and even N2 are anesthetic at high enough pressure.

Permalink to Comment

15. milkshake on January 21, 2010 10:09 PM writes...

Xe: good for all those places that your gerbil cannot reach

Permalink to Comment

16. Thomas Womack on January 22, 2010 5:19 AM writes...

Protein crystallographers are noted for using anything that you can think of and many things that you wouldn't (Os(NH3)6? Ta6Br14? Yb3+? diethylmercury? tetrathiomolybdate?) in the desperate hope of getting a heavy scatterer to bind coherently across their crystal; heavy-metal compounds that bind effectively to proteins are almost inevitably noxious persistent poisons, so high-pressure xenon and krypton chambers at least provide a different set of lab hazards ...

Permalink to Comment

17. anonymous on January 22, 2010 11:13 AM writes...

Interestingly, xenon CT is sometimes used as a diagnostic tool in ischemic stroke, e.g. http://www.neurology.org/cgi/content/full/72/13/1140 (this is still pretty exotic, though)

Could there be enough xenon still around to interfere with IV tPA, if there's still time to administer?

Permalink to Comment

18. Thomas Chung on January 23, 2010 1:15 AM writes...

@Hap - It says xenon lowers tPA brain hemorrhage, the biggest and worst adverse effect in tPA. But I suppose it inhibits tPA without lowering effectiveness? All quite bizarrely interesting.

Permalink to Comment

19. Al Hagedorn on January 23, 2010 11:49 AM writes...

Reminiscent of fluoride ion activating adenylate cyclase - we (briefly!) pondered SAR on that back in the '80s.

Permalink to Comment

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