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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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June 29, 2010

Stable Helical Peptides Can Do It All?

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Posted by Derek

Now, this could get quite interesting. A recent paper in PNAS talks about "downsizing" biologically active proteins to much shorter mimics of the alpha-helical parts of their structures. These show a good deal more stability than the parents, and show a sometimes startling amount of biological activity.

The building block for all this is the smallest helical peptide yet reported, a cyclic pentapeptide (KAAAD) curled as as a lactam between residues 1 and 5. Joining two or more of these up give you more turns, and replacing the alanines gives you plenty of possible mimics of endogenous proteins. An analog of nociceptin turned out to be the most potent agonist at ORL-1 ever described (40 picomolar), and an analog of RSV fusion protein is, in its turn, the most potent inhibitor of that viral fusion process ever found as well.

Meanwhile, the paper states that these constrained peptides were stable in human serum for over 24 hours, as very much opposed to their uncyclized counterparts, which are degraded rapidly. (Exocyclic amino acids, when present, do get degraded off in a time span of hours, though).

I'm quite amazed by all this, and I'm still processing it myself. I'll let the authors have the last word for now:

"This work is a blueprint for design and utility of constrained α-helices that can substitute for α-helical protein sequences as short as five amino acids. . .The promising conformational and chemical stability suggests many diverse applications in biology as molecular probes, drugs, diagnostics, and possibly even vaccines. The constrained peptides herein offer similar binding affinity and/or function as the proteins from which they were derived, with the same amino acid sequences that confer specificity, while retaining stability and solubility akin to small molecule therapeutics. . ."

Comments (12) + TrackBacks (0) | Category: Biological News


1. mikeymedchem on June 29, 2010 12:20 PM writes...

That's funny...looks an awful lot like Verdine's stapled peptides (which have all the properties you mentioned...), just constrained in a different way.

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2. anchor on June 29, 2010 1:45 PM writes...

#1 well said and I concur. More on this check below

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3. Billy T Fowler on June 29, 2010 1:59 PM writes...

Cyclization increases the overall performance of all drugs “schreiber showed this”. There is absolutely an astounding number of papers which show this over and over again. Cyclic drugs with the correct ring size have greater potency over linear compounds. In fact, the cyclic analogs out perform the linear opposition in every case when it posses the correct ring size to interact and bind with the target. The cyclic compound show better pharmacokinetics and can do what is almost impossible for small non-cyclic analogs. Cyclic compounds of ring size larger than 7 can mimic protein, protein interaction were small non-cyclic analogs are usually enzyme focused!

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4. Anonymous on June 29, 2010 4:59 PM writes...

of course, there wasn't much that was novel about Verdine's stapled peptides either. He just used metathesis, whereas other people made lactams. he did come up with a catchy name.

There are hundreds of papers about making constrained, alpha-helical peptides, and using those peptides to mimick larger protein surfaces. People have been doing this for years. I can't think of an example where it has led to anything useful...

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5. frequent visitor on June 29, 2010 6:56 PM writes...

Very Interesting! It kind of makes sense, a circle does give relatively "stable" 3D structure to hit targets in a specific conformation. In some ways remind me of Shih's work with DNA.

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6. Anonymous on June 29, 2010 8:18 PM writes...

So old, it's back in fashion again.

Look back at the 80s with such authors as Rivier, Veber, Goodman, Hruby.

Really - this is an ancient concept...

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7. bavarian on June 30, 2010 3:00 AM writes...

#6 Do not neglect the work of Horst Kessler. Cilengitide made it to Ph III.

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8. Fred on June 30, 2010 11:07 AM writes...

Anon: Is it as ancient as synthesizing small molecules to muck up biopolymers. What has been more exploited? Small molecules or cyclic peptides? If med chemists wernt such snobs our pipelines would be full of constrained peptides. constraining peptides creates structure and removes floppy N & C termini that are easily degraded. Strucute induces structure and structure is function. Hematide is a homodimer of two cyclic peptides that mimics EPO. It has pM activity as well. MEd chem needs to work cooperatively with biologically generated diversity to create constraints and higher order structures. I call it "conformational focusing" I am looking for VC money:)

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9. newnickname on July 1, 2010 10:11 PM writes...

Biphenyls, terphenyls, et seq. go in and out of favor. Because the Ph rings are not coplanar, you get a coil that disposes substituents in space very close to where poly-peptide sidechains would be in the corresponding alpha helix.

Maybe it's time to repeat that work and claim it as new ... again.

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10. Compute on July 7, 2010 4:57 AM writes...

The MDM2 - p53 story is a great example of how these peptide approaches have worked well at producing, first proof of concept/target validation, then later very reasonable small molecule mimetics as clinical candidates.

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11. Porsha Juedes on August 18, 2012 9:49 AM writes...

I truly enjoy reading on this internet site , it has got great blog posts. "I have a new philosophy. I'm only going to dread one day at a time." by Charles M. Schulz.

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12. Loyd Harber on October 10, 2015 11:47 AM writes...

Dude. Where is Comic Sans MS ??

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