More troubles for the poor pharmacologist.

As if drug chemists and pharmacologists didn’t have enough problems with downsizing and all, the following paper [ Proc. Natl. Acad. Sci. vol. 108 pp. 16819 – 16824 ’11 ] really throws them a curveball.  It’s about miraculin, a protein isolated from the berries of a West-African plant.  It contains 191 amino acids, is glycosylated and has no taste on its own.  It’s named miraculin, because, put it on your tongue, and substances which normally taste sour then taste sweet to you for an hour or two.

The neurophysiology of taste is becoming well worked out, and protein receptors for various tastes are known.  They turn out to be  G protein coupled receptors (GPCRs) embedded in the outer membranes of sensory cells on the tongue.  Pharmacologists are well acquainted with them, as GPCRs  are targets for 30% of the drugs in current use.  For an excellent review of their structure and how they work see http://wavefunction.fieldofscience.com/2011/10/gpcr-modeling-devil-hasnt-left-details.html.

The receptors for sweet tasting substances are named hT1R2 and hT1R3.  Miraculin blocks them at neutral pH (e.g. acts as an antagonist), but acts as an agonist as pH drops. Basically, anything acid (citric acid etc. etc.) tastes sour.

So here we have  the same substance acting as an antagonist at one pH and an agonist at another.  Could any of the 30% of all drugs acting on GPCRs do something similar?  Do large pH changes occur in pathologic conditions?  You bet, any area of the body not getting adequate circulation (think stroke, think heart attack, think the interior of a tumor) has a lower pH than it normally has.

So maybe even our best studied drugs may be two faced, having different pharmacologic effects depending on pH.

Along these lines, I’m far from convinced we understand all the things our drugs do, primarily because we don’t understand enough about what is going on inside our cells.  Take valproic acid (4 carboxy heptane) — a great anticonvulsant, found by accident as the solvent used to dissolve other drugs for epilepsy.  We thought it worked by inhibiting an enzyme destroying the major inhibitory neurotransmitter of the brain (gamma amino butyric acid, aka GABA), increasing brain inhibition and stopping seizures in their tracks.  However there is evidence that valproic acid inhibits histone deacetylases (HDACs) with potentially profound effects on gene expression. We now know that given during pregnancy valproic acid increases the first of a congenital malformation.  For details about histone deacetylases and epigenetics in general see https://luysii.wordpress.com/2011/09/15/molecular-biology-survival-guide-for-chemists-iv-epigenetics/

An even more amazing example of how little we know about how our drugs work can be found in an earlier post — https://luysii.wordpress.com/2011/02/02/medicinal-chemists-do-you-know-where-your-drug-is-and-what-it-is-doing/

It’s scary.  No wonder big pharma is having such problems.  The low lying fruit has been picked, and we don’t know enough about what’s going on to really know where to look.

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Comments

  • Curious Wavefunction  On October 21, 2011 at 3:51 pm

    Pretty interesting and seems to be a great example of how subtle changes (in this case probably related to the ionization state of a key protein residue) can change ligand behavior from antagonist to agonist. It could also be a consequence of the amazing phenomenon of functional selectivity which I have often mentioned.

    As for the relevance of pH in therapeutic intervention, one of my colleagues in grad school was trying to design compounds for the NMDA receptor which demonstrated the greatest difference in receptor inhibition at two different pH values. The indication, as you alluded to, was stroke. The goal was a drug that would inhibit the receptor most during a stroke (when the local pH dropped) but would not measurably inhibit it otherwise at normal pH. Good stuff.

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