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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: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

« Up Periscope And Fire All Bow Tubes | Main | Levoglucosan »

October 18, 2006

Peptides as Texts

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Posted by Derek

There's a curious paper (subscriber-only link) in the latest Nature that's getting some attention, titled "A linguistic model for the rational design of antimicrobial peptides". For non-subscribers, here's a synopsis of the work from the magazine's news site.

A group at MIT headed by Gregory Stephanopolous has been studying various antimicrobial peptides, which are secreted by all kinds of organisms as antibiotics. Taking the amino acid sequences of several hundred of these and feeding them into a linguistic pattern-analysing program suggested some common features, which they then used to synthesize 42 new unnatural candidates. The hit rate for these was about 50%, which is far, far more than you'd expect if you weren't tuning in to some sort of useful rules.

It's the concept of "peptide grammar" that seems to be the news hook here. But I'm quite puzzled by all the fuss, because looking for homology among protein sequences is one of the basic bioinformatics tools. I have to wonder what the MIT group found with their linguistics program that they wouldn't have found with biology software. What they're doing is good old structure-activity relationship work, the lifeblood of every medicinal chemist. Well, it's perhaps better described as sequence-activity relationships, but sequence is just a code for structure. There's nothing here that any drug company's bioinformatics people wouldn't be able to do for you, as far as I can see.

So why haven't they? Well, despite the article's mention of a potential 50,000 further peptides of this type, the reason is probably because not many people care. After all, we're talking about small peptides here, of the sort that are typically just awful candidates for real-world drugs. And I'm not just babbling theory here - many people have actually tried for many years now to commercialize various antimicrobial peptides and landed flat on their faces.

You won't see a mention of that history in the Nature news story, unfortunately. They do, to their credit, mention (albeit in the fourth paragraph from the end) that peptides are troublesome development candidates. That's where it also says that there are reports that bacteria can become resistant even to these proteins, which prompts me to remind everyone that bacteria can become resistant to everything short of freshly extruded magma. It's in the very last paragraph of the story, though, that Robert Hancock of UBC in Vancouver says just what I was thinking when I started reading:

(Hancock) questions how different the linguistics technique is from other computational methods used to find similarities between protein sequences. "What's new is the catchy title," he says.

Comments (10) + TrackBacks (0) | Category: Biological News | Drug Development | Infectious Diseases


COMMENTS

1. John Thacker on October 19, 2006 7:12 AM writes...

Yeah. For example, Hidden Markov Models are common in both linguistics and in protein and genetic sequencing. If you ran HMM programs originally written for linguistics on protein sequences, you wouldn't really call it a "new technique from linguistics."

Permalink to Comment

2. A-non-y-mous on October 19, 2006 7:44 AM writes...

As a "peptide guy", all I can say is: what a load of crap (the paper, not you Derek). The fact is, antimicrobial peptides are a dime a dozen, and not hard to "design", either through rational point-mutations or dumb luck.

From an academic view, it's a good paper. It's multi-disciplinary (look at where the authors are from!), the flava-of-the-day. It's got a catchy title, thus bound to get peoples attention. It's probably got a bunch of sweet-looking PowerPoint slides when he goes on the lecture circuit. All of this will help him get funding from the NIH, which is very tough recently. So more power to him.

Also, stuff like this helps justify the MIT Biopolymers Lab. My guess is that the Biopolymers Lab is up for funding again and they need a quick paper to justify its existence.

Now, time for my coffee.

Permalink to Comment

3. d_orbital on October 19, 2006 8:09 AM writes...

Now I'm not sold on this work by any means, but lets try and see further down the road. Sure this linguistics trick isn't any better (or worse?) than biology software, and surely the peptide candidates are problemmatic. But, it is a proof of concept and it may lead to (or inspire) some truly novel and useful stuff downstream. Of course, it might not.

On more of a semantics note, how often does one pump out a "quick" paper to Nature? :)

Permalink to Comment

4. GATC on October 19, 2006 9:54 AM writes...

More dribble from "academentia", obviously another slow news day on campus. Better to be a radioastronomer when looking for these types of patterns. But then again, can you say "maganin", "lysostaphin", "nisin", etc. Nisin is in use right now as a food preservative; lysostaphin creams are used as antistaphylococcal topicals (also currently under review for systemic indications), and look how far Pexiganan (MSI-78) made it for diabetic foot-ulcer infections before it died a slow death. There was little or no reisitance found for that class (magainins) which at the time was a major concern since these molecules are produced by vertebrates and there were human orthologs critical for inate immunity. Similarlily, the whole bacterial lantibiotic story is fascinating, particularly with regard to the similarities seen with other small peptides produced by Gram-positives that act as intercellular signaling molecules (streptococcal competence factors for example).

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5. Derek Lowe on October 19, 2006 9:58 AM writes...

I had some stock in Magainin Pharmaceuticals at the time, so I saw their peptide die at close range. The company's now renamed and re-focused, and slowly sinking into the primordial ooze, as far as I can see.

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6. GATC on October 19, 2006 10:20 AM writes...

Yea, asthma I hear. Too bad. One of the founders and discoverer of magainin-1, Mike Zasloff, was a hell of a good guy (still is for that matter). We would have been much better off if folks like him, Venter, etc. would have stayed at the NIH and continued doing good work. Unfortunately, that place kind'a stiffles that sort of thing.

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7. DLIB on October 19, 2006 11:44 AM writes...

Seems like they're taking cues from the infamous MIT Media lab ( the engineering equivalent for "catchiness").

Permalink to Comment

8. Darth_Bubbster on October 19, 2006 12:12 PM writes...

When I worked in protein design, I was always trying to get ELVISLIVES in the sequence. With these guys PR machine, I might have been able to get the cover of TIME.

Permalink to Comment

9. Dave H on October 19, 2006 2:44 PM writes...

Funny, I own some re-named Magainin (Geneara). They are still disapointing. As for "bacteria can become resistant to everything" check these guys out:

http://www.byotrol.com/news.php

Permalink to Comment

10. RKN on October 19, 2006 5:19 PM writes...

Darth_Bubbster,

That was funny. Just for the fun of it I did a short sequence BLAST at ncbi. Evidently a polymorph of elvis lives in polyketide synthase:

mnappyslaa kelanaealq eliisllves leeeqidped idlrqplgsy glssvqalvl lgklekqvgf alsptvlwny ptiqalagwl veeieaaahr qei

Loss of function, wanna bet?

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