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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 9, 2013

Mass Spec Continues Its Conquests

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Posted by Derek

You know, mass spectrometry has been gradually taking over the world. Well, maybe not your world, but mine (and that of a lot of biopharma/biophysical researchers). There are just so many things that you can do with modern instrumentation that the assays and techniques just keep on coming.

This paper from a recent Angewandte Chemie is a good example. They're looking at post-translational modifications of proteins, which has always been a big field, and shows no signs of getting any smaller. The specific example here is SIRT1, an old friend to readers of this site, and the MALDI-based assay reported is a nice alternative to the fluorescence-based assays in that area, which have (notoriously) been shown to cause artifacts. The mass spec can directly detect deacetylation of a 16-mer histone H4 peptide - no labels needed.

The authors then screened a library of about 5500 natural product compounds (5 compounds per well in 384-well plates). As they showed, though, the hit rates observed would support higher pool numbers, and they successfully tested mixtures of up to 30 compounds at a time. Several structures were found to be micromolar inhibitors of the deacetylation reaction. None of these look very interesting or important per se, although some of them may find use as tool compounds. But the levels of detection and the throughput make me think that this might be a very useful technique for screening a fragment library.

Interestingly, they were also able to run the assay in the other direction, looking at acetylation of the histone protein, and discovered a new inhibitor of that process as well. These results prompted the authors to speculate that their assay conditions would be useful for a whole range of protein-modifying targets, and they may well be right.

So if this is such a good idea, why hasn't it been done before? The answer is that it has, especially if you go beyond the "open literature" and into the patents. Here, for example, is a 2009 application from Sirtris (who else?) on deacetylation/acetylation mass spec assays. And here's a paper (PDF) from 2009 (also in Angewandte) that used shorter peptides (6-mers) to profile enzymes of this type as well. There are many other assays of this sort that have been reported, or worked out inside various biopharma companies for their own uses. But this latest paper serves to show people (or remind them) that you can do such things on realistic substrates, with good reproducibility and throughput, and without having to think for a moment about coupled assays, scintillation plates, fluorescence windows, tagged proteins, and all the other typical details. Other things being equal, the more label-free your assay conditions, the better off you are. And other things are getting closer equal all the time.

Comments (3) + TrackBacks (0) | Category: Analytical Chemistry | Drug Assays


1. Dr Robert on April 10, 2013 4:58 AM writes...

MS-based assays are definitely the way forward in this area and I appreciate the authors' work with regard to optimising the procedure. However, also considering the previous work referenced by Derek, is that something to be published in Angewandte? Don't get me wrong, I'm very much in favour of chemical biology/med chem and it's not about being negative but this seems oversold to me.

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2. SteveM on April 10, 2013 7:31 PM writes...

Yeah. And parenthetically, media lay people may ooh! and ahh! over the brain imaging work done by the neuro-physiologists and neuro-psychiatrists who are feted on Charlie Rose.

But the real genii behind the imaging curtain are the unseen and unappreciated physicists and mathematical algorithm guys that do the computational computing to generate the images in the first place.

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3. Phil on April 12, 2013 1:28 PM writes...

Academia is posied to dominate this sort of analysis given its obvious connections to Analytical Chemistry expertise.

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