Tidings of great joy (for synthetic organic chemists anyway)

Anyone reading “In the Pipeline” knows that the past year has been grim for synthetic organic chemists in the drug industry.  Everyone and his dog is chasing kinase inhibitors.  The following paper produces a whole new set of potential therapeutic targets (along with obvious organic compounds to make to hit the target). With 20/20 hindsight the work was screamingly obvious  (I didn’t think of it either).

Drug chemists are always looking for molecules which bind to proteins altering their function(s).  It’s been known for  years that feedback inhibition of an early member of a synthetic enzyme chain by the ultimate product of the chain (invariably a small molecule) occurs. Then there are the riboswitches in which small molecules bind to messenger RNA and prevent its translation (but these are only seen in bacteria). Still riboswitches provide a possible target for a new class of antibacterials (which, as far as I know hasn’t been explored to any extent).

One slightly more obscure example, but quite similar to what the paper describes.  2,3 bisphosphoglyceric acid (2,3 BPG) is an intermediary metabolite produced by the breakdown of glucose when oxygen is not available (this is known as anaerobic glycolysis).   Guess what it does. It binds to hemoglobin causing it to give up its oxygen more readily — just what an oxygen starved cell needs.  The binding isn’t to the site where hemoglobin binds oxygen, but elsewhere, making it a classic allosteric effect.

So small metabolic intermediates can alter the function of proteins by binding to them.  Hmm.  Why not look for more of this?  That’s exactly what the paper did (but on a rather limited scale, although the technique could easily be generalized).

Here it is.  [ Cell vol. 143 pp. 639 – 650 ’10 ]. A mass spectrometry assay for the large scale identification of in vivo hydrophobic small metabolite interactions (under 1000 Daltons) in yeast was developed. They looked at metabolites that bound to proteins in the ergosterol biosynthetic pathway and also protein kinases (a pretty small subset of all yeast proteins but here are the protein kinases again). Many of these proteins bind small metabolites. The vast majority of these protein/metabolic interactions were unknown before. Many key regulatory proteins such as protein kinases bind metabolites. Ergosterol binds many proteins (e.g. Ypk1, a mammalian AKT/SGK kinase homolog — but it regulates the activity of this particular one). Some 682 metabolic compounds have been found in yeast. What they did was tag proteins with an protein domain which could bind immunoglobulin G (IgG), isolate the protein with a magnetic bead coated with IgG, and then see what the metabolites bound to it actually were. 20% of the protein kinases they studied bound hydrophobic molecules (they didn’t analyze hydrophilic small molecules). Only a limited number of metabolites were found to be bound to any particular protein. The stoichiometry is usually on the order of 1:1 or 1:2 implying very specific interactions.

Can you say druggable targets?  There are several problems with this approach, all of which have to do with our incomplete knowledge of what’s going on inside our cells.  First, you could do this with a protein of (relatively) known function — say p53, but we don’t know any functions of many proteins and of those we have some idea about, our knowledge is incomplete.  Second, if you’re targeting a disease of semi-unknown cause (say Alzheimer’s), you could see what small metabolites are binding to the known culprits (gamma secretase — with its four components, the amyloid precursor protein, tau), but even finding them might be barking up the wrong tree, if the known culprits turn out to be innocent bystanders, or mere accomplices.  Third, if you’re targeting cancer, there are simply too many targets.  Now that the genome of several types of cancer cells are in, the average number of mutations in protein coding genes in, say breast cancer, is 93 [ Science vol. 313 p. 1370 ’06 ].

Nonethless the game is on.  I’m sure it wouldn’t be hard to think of a synthetic analogue of 2, 3 bis phophoglyceric acid (only 3 carbons, one carboxyl, and 2 phosphoesters), maybe it would help the huge number of people with chronic lung disease.

Happy new year.

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