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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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« Fuzeon's Fallout | Main | Hexacyclinol Rides Again »

July 20, 2006

Peptide Craziness

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Posted by Derek

Since I was talking about peptide synthesis yesterday, and the usefulness of peptides in general, I thought a few back-of-the-envelope calculations would be interesting. After all, if we're going to be making the things, we should know what we're getting into.

How about a combichem library of the things? Let's see. . .since someone mentioned vasopressin and oxytocin, let's figure that other 9-mers could have some interesting activity. What if we want them all? With the twenty most common amino acids in hand, and our peptide synthesizer machines recently serviced and reloaded, we throw the switch and. . .a mere five hundred and twelve billion peptides later, our library is ready for screening.

Ahem. That's well more than ten thousand times the number of organic substances that are indexed in Chemical Abstracts. This exponential stuff gets out of hand pretty quickly. Storing the stuff will be a problem. At, say, ten milligrams per compound, we're looking at five million kilos of peptides, and that's before the glass vials are added in. Protein folks look aghast if you talk about producing as much as ten milligrams of any given peptide, but hey, if we're going to turn the things into drugs, we have to get ready to work on scale.

And if we're going to make drugs, we're probably going to have to deal with some unnatural amino acids to improve metabolic stability. That has an effect, too, as you'd figure. Adding in one extra gives you an extra two hundred and seventy billion peptides, which is certainly value for your synthesis dollar. If you're going to get the deluxe package, with the D and L forms of the nineteen chiral ones, that'll run your screening file up to 200 trillion total, which is going to put a real strain on the chemical synthesis capacity of the entire world economy. Call ahead.

So a library of 26-mers, the size of Fuzeon, is going to be really hard to handle. That comes to a cool 6.71 times ten to the thirty-third power, which is beginning to get into the realm of really substantial numbers. At ten mgs per compound, we're down to the 6.7 times ten to the 25th metric tons, which is only a bit more than. . .ten thousand Earths. Well, ten thousand Earths made up of an even mixture of the twenty amino acids, that is, rather than boring old inorganic rock.

Let's just say that there's a lot of patent space, and plenty of reduction-to-practice loopholes, and leave it at that. . .

Comments (11) + TrackBacks (0) | Category: General Scientific News


1. J Brower on July 21, 2006 5:44 AM writes...

Are you serious? Sarcastic? For the first time in a while you are making no sense. No one in their right mind (as you point out?) is going to make a library of every combination for a 9-mer peptide. One would use the natural peptide as a "lead", perhaps do alanine scanning to pinpoint crucial amino acids, and modify from there. They'd probably make a few dozen peptides at most. The hardcore people might use phage display, and work from there.

Your diatribe is akin to finding a "lead" small molecule, say with a formula C50H78N12O8, and saying to yourself "Hey, lets make every single possible combination with this formula and see what we get!"

This route throws every principle of medicinal chemistry in the waste bottle, set on fire, and thrown out the window (the higher the better). My point is that whether working with peptides or small molecules, people use the same med chem principles and techniques, look for SARs, etc. They don't leave it up to chance and a random peptide generator.

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2. JoeW on July 21, 2006 8:02 AM writes...

Brower: I think he is kidding!

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3. Derek Lowe on July 21, 2006 8:02 AM writes...

Um, that post was. . .tongue-in-cheek, I guess is the phrase I'm looking for, and just designed to show how crazy biochemical diversity gets. Calm down.

And as far as throwing med-chem SAR principles out the window, remember the crazy part of the combichem boom in the early 1990s? I rest my case.

But I'm still not actually proposing the 9-mer library. Although, y'know, there have been times in the biotech industry when you could have attracted venture capital funding for the idea, with enough conviction in your voice and some really snazzy PowerPoints.

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4. J Brower on July 21, 2006 8:46 AM writes...

I understand your "tongue-in-cheek" post, apparently you didn't understand my point, which is not hostile, believe me! I should have used different wording, my sincere apologies.

My part about you not making sense is that the ridiculous number of possible peptides is equal to the number of small molecules that can be made, like you said, think combi-chem. Only peptide research is (for the most part) a lot more focused than combi-chem. This is one point that many, many researchers fail to grasp, and I hate to see peptide research lumped in with it. But, we see so many papers in which hundreds of compounds are made (non-combichem style), and they really are just throwing darts at a dart board, and refuse to realize that they, too, are making "random" compounds.

As far as patents, I have seen people patent 4-,5-, and 6-mers that covered nearly every possibility, for every conceivable application. Like you said, reduce that to practice!


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5. Dr. Peptide on July 21, 2006 9:14 AM writes...

Fuzeon is a 36 amino acid peptide. Where did the idea it is a 26mer come from? Also, did you hear the news from Trimeris on Wed? Fuzeon generated total global sales of $57.2 million in the second quarter of 2006, a 6 percent increase over a year earlier and its highest quarterly revenue total ever.

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6. Jose on July 21, 2006 10:42 AM writes...

Derek and others-

I am constantly amazed at the strange path from hit to lead; the decision trees are so hard to predict, and the final, optimized molecule often has little resemblance to the original. My question is, how in the world did so many people/companies convince themselves that this process could be replicated by combi libraries and strategies? Hindsight is obviously 20/20, but it seems amazing that there was such a collective delusion that diversity was equal to optimization.

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7. Chrispy on July 21, 2006 4:05 PM writes...

The cool thing about peptides is that you can gain access to them via biological techniques. So rather than synthesizing your libraries you could get bugs to do it and screen by phage display. Of course, your library size would still be limited to like 10e11, but you can make up for that with rounds of evolution.

Between Fuzeon and Hematide (a pegylated Epo agonist) we might well just be coming into the Era of the Peptide...

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8. Vince on July 21, 2006 10:53 PM writes...

Speaking of hematide- what an incredible construct! Who would think to add a polymer to a peptide. From the recent press release that I have read about manufacturing hematide, it sounds like the company American Peptide is years above the competition in their skill of PEGylating peptides. I would hedge my bets that the next generation of Fuzeon will be PEGylated.

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9. theodore price on July 22, 2006 6:51 PM writes...

How about letting the cells do all the work for you. Put the receptor and peptide sequence on a bicistronic vector where the peptide sequence can be randomly generated to yeild small peptides of interest. Then put them into a cell line containing another sequence that the cell can be dependent on for survival when it is exposed to some chemical. If the transcritpion of the survival gene can be made such that it is downstream of the peptide-receptor vector, you could have a whole screen that required no work other than transfection. Just an idea...

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10. Glenn McEnroe on July 28, 2006 9:16 PM writes...

If fuzeon were really a 26 mer it would have been beat by the record set with the production of calcitonin a 32 mer that was produced by synthetic route long before the age of recombinant protein production. I hope Roche really needs all 36 residues for activity otherwise it would be a waste. I can't imagine that a synthetic route for this large a peptide is more efficient than recombinant product which is probably used for peptides such as hBNP also a 32 mer. I have to say the pictures of their production facility are quite impressive though.

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11. John on March 31, 2008 11:49 PM writes...

Five hundred and twelve billion peptides is a pretty large number of peptides. More seriously, you can get companies to make custom peptide libraries for you. You can purchase them as microarrays, on plates, or you can find companies that will express the peptides via phage display (though un-natural amino acids are out of the question for the last option). Phage display is a more viable option which may be less prone to difficulties associated with peptide length and hydrophobicity often experienced using customary peptide synthesis techniques (the Peptide Resource Page - - has a good custom peptide synthesis section). It is also probably more practical to make larger numbers of peptides on a phage surface as well. Combinatorial chemistry has been given a bad rap over the years, but there is always some value in approaching drug design with a "focused diversity" approach - i.e. an approach that incorporates both a little rational/practical design and combinatorial thinking.

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