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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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July 27, 2011

Bait And Switch For Type B GPCRs

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Posted by Derek

You hear often about how many marketed drugs target G-protein coupled receptors (GPCRs). And it's true, but not all GPCRs are created equal. There's a family of them (the Class B receptors) that has a number of important drug targets in it, but getting small-molecule drugs to hit them has been a real chore. There's Glucagon, CRF, GHRH, GLP-1, PACAP and plenty more, but they all recognize good-sized peptides as ligands, not friendly little small molecules. Drug-sized things have been found that affect a few of these receptors, but it has not been easy, and pretty much all of them have been antagonists. (That makes sense, because it's almost always easier to block some binding event rather than hitting the switch just the right way to turn a receptor on).

That peptide-to-receptor binding also means that we don't know nearly as much about what's going on in the receptor as we do for the small-molecule GPCRs, either (and there are still plenty of mysteries around even those). The generally accepted model is a two-step process: there's an extra section of the receptor protein that sticks out and recognizes the C-terminal end of the peptide ligand first. Once that's bound, the N-terminal part of the peptide ligand binds into the seven-transmembrane-domain part of the receptor. The first part of that process is a lot more well-worked-out than the second.

Now a German team has reported an interesting approach that might help to clear some things up. They synthesized a C-terminal peptide that was expected to bind to the extracellular domain of the CRF receptor, and made it with an azide coming off its N-terminal end. (Many of you will now have guessed where this is going!) Then they took a weak peptide agonist piece and decorated its end with an acetylene. Doing the triazole-forming "click" reaction between the two gave a nanomolar agonist for the receptor, revving up the activity of the second peptide by at least 10,000x.

This confirms the general feeling that the middle parts of the peptide ligands in this class are just spacers to hold the two business ends together in the right places. But it's a lot easier to run the "click" reaction than it is to make long peptides, so you can mix and match pieces more quickly. That's what this group did next, settling on a 12-amino-acid sequence as their starting point for the agonist peptide and running variations on it.

Out of 89 successful couplings to the carrier protein, 70 of the new combinations lowered the activity (or got rid of it completely). 15 were about the same as the original sequence, but 11 of them were actually more potent. Combining those single-point changes into "greatest-hit" sequences led to some really potent compounds, down to picomolar levels. And by that time, they found that they could get rid of the tethered carrier protein part, ending up with a nanomolar agonist peptide that only does the GPCR-binding part and bypasses the extracellular domain completely. (Interestingly, this one had five non-natural amino acid substitutions).

Now that's a surprise. Part of the generally accepted model for binding had the receptor changing shape during that first extracellular binding event, but in the case of these new peptides, that's clearly not happening. These things are acting more like the small-molecule GPCR agonists and just going directly into the receptor to do their thing. The authors suggest that this "carrier-conjugate" approach should speed up screening of new ligands for the other receptors in this category, and should be adaptable to molecules that aren't peptides at all. That would be quite interesting indeed: leave the carrier on until you have enough potency to get rid of it.

Comments (3) + TrackBacks (0) | Category: Biological News | Chemical News | Drug Assays


1. Rick on July 27, 2011 10:23 AM writes...

That IS clever. It reminds me of using stochastic resonance to amplify otherwise undetectable signals. In this case, you can fish for interesting screening hits in a sea of 0.1 mM compounds that you would otherwise discard for being too wimpy. I wonder how many other non-GPCR targets this conceptual approach could be applied to. Completely agree that one early med chem objective MUST be achieving potencies that eliminate the need for the co-agonist or co-antagonist. It is a potentially useful early screening tool, but should NOT be considered a way to make crappy drugs better.

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2. GG on July 28, 2011 7:33 AM writes...

Interesting approach...but I have a completely unrelated comment. You used a turn of phrase that is commone in science and I don't understand why: "...a german team...", this adds no useful information to the sentence but people often use this when refering to science outside of their own country.

Sorry to hijack the comments for such a triviality, but I usually see it in print where I cannot solicit opinions.

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3. Derek Lowe on July 28, 2011 9:28 AM writes...

GG, in this case it's just shorthand because I didn't want to take up the room for the full affiliations of everyone involved. In this case, the authors were from the Max-Planck Institute of Psychiatry in Munich, and the Institute of Developmental Genetics at the Helmholz Zentrum. And one of the corresponding authors is now at Oxford. I could have just as well have said "a team from Munich", but that's in the same way that I might have said "A team from Boston".

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