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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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August 26, 2008

New, Improved DNA?

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Posted by Derek

As all organic chemists who follow the literature know, over the last few years there’s been a strong swell of papers using Barry Sharpless’s “click chemistry” triazole-forming reactions. These reaction let you form five-membered triazole rings from two not-very-reactive partners, an azide and an acetylene, and people have been putting them to all kinds of uses, from the trivial to the very interesting indeed.

In the former category are papers that boil down to “We made triazoles from some acetylenes and azides that no one else has gotten around to using yet, and here they are, for some reason”. There are fewer of those publications than there were a couple of years ago, but they’re still out there. For its part, the latter (interesting) category is really all over the place, from in vivo biological applications to nanotechnology and materials science.

One recent paper in Organic Letters which was called to my attention starts off looking as if it’s going to be another bit of flotsam from the first group, but by the end it’s a very different thing indeed. The authors (from the Isobe group at Tohoku University in Japan, with collaborators from Tokyo) have made an analog of thymine, the T in the genetic code, where the 2-deoxyribose part has both an azide and an acetylene built onto it.

So far, so good, and at one point you probably could have gotten a paper out of things right there – let ‘em rip to make a few poly-triazole things and send off the manuscript. But this is a more complete piece of work. For one thing, they’ve made sure that their acetylenes can have removable silyl groups on them. That lets you turn their click reactivity on and off, since the copper-catalyzed reaction needs a free alkyne out there. So starting from a resin-supported sugar, they did one triazole click reaction after another in a controlled fashion – it took some messing around with the conditions, but they worked it out pretty smoothly.

And since the acetylene was at the 5 position of the sugar, and the azide was at the 3, they built a sort of poly-T oligonucleotide – but one that’s linked together by triazoles where instead of the phosphate groups found in DNA. People have, of course, made all sorts of DNA analogs, with all sorts of replacements for the phosphates, but they vary in how well they mimic the real thing. Startlingly, when they took a 10-mer of their “TL-DNA” (triazole-linked) and exposed it to a complementary 10-residue strand of good ol' poly-A DNA, the two zipped right up. In fact, the resulting helix seems to be significantly stronger than native DNA, as measured by a large increase in melting point. (That's their molecular model of the complex below left).Triazole%20DNA.jpg

Well, after reading this paper, my first thought was that it might eventually make me eat some of my other words. Because just last week I was saying things about the prospects for nucleic acid therapies (RNAi, antisense) - mean, horrible, nasty things, according to a few of the comments that piled up, about how these might be rather hard to implement. But when I saw the end of this paper, the first thing that popped into my head was "stable high-affinity antisense DNA backbone. Holy cow". I assume that this also crossed the minds of the authors, and of some of the paper's other readers. Given the potential of the field, I would also assume that eventually we'll see that idea put to a test. It's a long way from being something that works, but it sure looks like a good thing to take a look at, doesn't it?

Comments (10) + TrackBacks (0) | Category: Biological News


COMMENTS

1. Eli on August 26, 2008 8:34 AM writes...

I fail to see how using this approach to build an oligomer for potential antisense applications is any different or better than using PNA, which, I believe, doesn't work too well in vivo, does it?

Permalink to Comment

2. 2cents on August 26, 2008 8:41 AM writes...

There are numerous caveats with using polyT/poly A systems. A big one being non specific intereactions. I would have preferred a more traditional poly T with GC clamps at the ends. I bet in those type of sequences you will see very different results. I also dont remember seeing any melting transitions in the paper - which probably means that they were too ugly to include into the text.

Also, a number of un-charged stabilized DNA backbones already exist and have been explored with limited success. So I wouldnt hold my breath with this one. Seems to be another example of "lets click" something together are publish it.

Permalink to Comment

3. Derek Lowe on August 26, 2008 8:48 AM writes...

Well, that's what's unknown here - the first thing to do would be to check the cellular uptake of these things, and see if you're ahead or behind what's known with PNA or the like. I have no idea what they'll do, but triazoles are rather different from peptides, so it's worth a look. And the melting point increase makes this look at least as stable, or perhaps even more stable, than the PNA hybrid.

Permalink to Comment

4. HelicalZz on August 26, 2008 8:54 AM writes...

There are quite a few modifications that stabilize a helix. Eli mentions PNA which I worked with for years, but add locked nucleic acids as a promising alteration as well. As with PNA, the triazole linkage should benefit from a lack of charge-charge repulsion between strands. But whether there is a specificity fall-off remains to be seen.

It isn't all about therapeutics though, look for diagnostic applications first.

Permalink to Comment

5. qetzal on August 26, 2008 9:13 AM writes...

I agree with the notes of caution raised by prevous commenters.

In additioni, things like antisense and RNAi generally require downstream events that alter gene expression. Simple base pairing alone isn't enough.

Even if you can make this stuff, get it into cells, and have it base pair specifically with a target mRNA, there's no guarantee it will be recognized by the processing machinery needed to achieve an antisense or RNAi effect.

(Also, IIRC, some DNA analogs make great duplexes when you're just binding oligo-T to poly-A. Later, when you make a mixed sequence oligo with your new chemistry, you may find it doesn't base pair very well after all.)

Permalink to Comment

6. such.ire on August 26, 2008 9:38 AM writes...

I'm putting my money on LNA-DNA hybrids and gap-mers right now. RNase H-dependent catalytic activity, plus long serum half-lives, good cellular uptake in primates, and seemingly high specificity make it seem like pretty good technology.

Permalink to Comment

7. Hello_World on August 26, 2008 9:44 AM writes...

I think we can all agree that you maybe go a little overexcited about this paper, Derek? Although not a bad little paper - this is hardly a major step forward in this field. I guess the best that can be said about it is "let's see how this one does."

Permalink to Comment

8. Wavefunction on August 26, 2008 1:16 PM writes...

Off topic...but you might find this interesting:
"Drug Research Needs Serendipity"
http://www.ft.com/cms/s/0/b735787c-5d9b-11dd-8129-000077b07658.html?nclick_check=1

Permalink to Comment

9. MTK on August 26, 2008 3:16 PM writes...

Tangentially related:

What can you do synthetically with a triazole?

It's a great little reaction to form the heterocycle, so can you transform that heterocycle into something else or is that about it? Hydrogenolysis?

Permalink to Comment

10. Morten on August 27, 2008 3:52 AM writes...

Agree with such.ire
LNA is doing it and probably better. Go to Exiqon's website for the details.

Permalink to Comment

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