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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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November 3, 2010

TRIM21: A Cure For the Common Cold? Maybe Not. . .

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Posted by Derek

This article is getting the "cure for the common cold" push in a number of newspaper headlines and blog posts. I'm always alert for those, because, as a medicinal chemist, I can tell you that finding a c-for-the-c-c is actually very hard. So how does this one look?

I'd say that this falls into the "interesting discovery, confused reporting" category, which is a broad one. The Cambridge team whose work is getting all the press has actually found something that's very much worth knowing: that antibodies actually work inside human cells. Turns out that when antibody-tagged viral particles are taken up into cells, they mark the viruses for destruction in the proteosome, an organelle that's been accurately compared to an industrial crushing machine at a recycling center. No one knew this up until now - the thought had been that once a virus succeeds in entering the cell, that the game was pretty much up. But now we know that there is a last line of defense.

Some of the press coverage makes it sound as if this is some new process, a trick that cells have now been taught to perform. But the point is that they've been doing it all along (at least to nonenveloped viruses with antibodies on them), and that we've just now caught on. Unfortunately, that means that all our viral epidemics take place in the face of this mechanism (although they'd presumably be even worse without it). So where does this "cure for the common cold" stuff come in?

That looks like confusion over the mechanism to me. Let's go to the real paper, which is open-access in PNAS. The key protein in this process has been identified as tripartite-motif 21 (TRIM21), which recognized immunoglobin G and binds (extremely tightly, sub-nanomolar) to antibodies. This same group identified this protein a few years ago, and found that it's highly conserved across many species, and binds an antibody region that never changes - strong clues that it's up to something important.

Another region of TRIM21 suggested what that might be. It has a domain that's associated with ubiquitin ligase activity, and tagging something inside the cell with ubiquitin is like slapping a waste-disposal tag on it. Ubiquinated proteins tend to either get consumed where they stand or dragged off to the proteosome. And sure enough, a compound that's known to inhibit the action of the proteosome also wiped out the TRIM21-based activity. A number of other tests (for levels of ubiquitination, localization within the cell, and so on) all point in the same direction, so this looks pretty solid.

But how do you turn this into a therapy, then? The newspaper articles have suggested it as a nasal spray, which raises some interesting questions. (Giving it orally is a nonstarter, I'd think: with rare exceptions, we tend to just digest every protein that gets into the gut, so all a TRIM21 pill would do is provide you with a tiny (and expensive) protein supplement). Remember, this is an intracellular mechanism; there's presumably not much of a role for TRIM21 outside the cell. Would a virus/antibody/TRIM21 complex even get inside the cell to be degraded? On the other hand, if that kept the virus from even entering the cell, that would be an effective therapy all its own, albeit through a different mechanism than ever intended.

But hold on: there must be some reason why this mechanism doesn't always work perfectly - otherwise, no nonenveloped virus would have much of a chance. My guess is that the TRIM21 pathway is pretty efficient, but that enough viral particles miss getting labeled by antibodies to keep it from always triggering. If that's true, then TRIM21 isn't the limiting factor here - it's antibody response. If that's true, then it could be tough to rev up this pathway.

Still, these are early days. I'm very happy to see this work, because it shows us (again) how much we don't know about some very important cellular processes. Until this week, no one ever realized that there was such a thing as an intracellular antibody response. What else don't we know?

Comments (16) + TrackBacks (0) | Category: Biological News | Infectious Diseases


1. watcher on November 3, 2010 8:14 AM writes...

Your postings seem to be getting longer. I don't have the time to read them.

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2. Smoki on November 3, 2010 8:16 AM writes...

I would also think that the antibody response is the limiting factor.

I wouldn't say that the TRIM-based mechanism does not work perfectly. Possibly this mechanism contributes to why the Common Cold normally only lasts a few days and not longer. Once the body starts producing large quantities of tightly-binding antibodies, the cells can chew easily on TRIM-labelled viruses. But before you mount a good antibody response, this mechanism is probably not sufficient to stop the disease.

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3. PTM on November 3, 2010 11:48 AM writes...

Interesting and important discovery, but as you say there is nothing here to suggest a cure for common cold.

Also the proteasome is probably only a part of the whole response, although degrading proteins may be enough to disrupt infection in some cases, for the response to be most effective genetic material should be degraded as well. This would imply there are some nucleases involved too.

Containment may also be needed as the cell has to somehow prevent the virus from escaping. The virus doesn't need its coat once in the cell so just tagging coat proteins for degradation is not enough.

All in all, even knowing that proteasome is involved, it is far from obvious how the cell manages to neutralize viruses tagged in this way, but at least now that this mechanism is known to exist it can be studied in more detail.

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4. ex-Pfizerite on November 3, 2010 11:51 AM writes...

Agouron had a rhinovirus project with two anti-viral compounds in the clinic AG7088 and AG7404. Unfortunately you need to take the drug within 24 hours of onset of symptoms and as they say results may vary.

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5. Darth Continent on November 3, 2010 12:38 PM writes...

Interesting article. I guess if you take "research" quite literally, science necessitates REsearching previously studied systems as new tools emerge that let us more effectively crack the system's code.

A bit scary to think how stale some research endeavors might be, for example, if the wheel isn't squeaky enough to get the grease of funding?

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6. Dennis on November 3, 2010 1:07 PM writes...

I hate to nitpick, but is the proteasome really considered an organelle?

Actually, that's a lie. I love to nitpick.

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7. Spork on November 3, 2010 3:00 PM writes...

As far as a therapy goes, it seems to me that if you stuck TRIM21 (or enough of it to be recognized by the cell) To some nonspecific antibodies, or other sticky molecules, you could effectively label all or at least almost all macromolecules that manage to enter the cell for recycling, rhinoviruses included.

Not being a biologist, however, I have no idea just how destructive this approach might be to the sinus.

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8. You're Pfizered on November 3, 2010 3:55 PM writes...

Winter vomiting?

A vaccine for the common cold is the holy grail, not a treatment that trims the effects by a day or two, not unless it's really inexpensive.

The applications for the more serious, life-threatening issues is where this concept could bear fruit.

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9. Watson on November 3, 2010 5:33 PM writes...

Perhaps this hypothetical therapy could be delivered by one of those cool Nativis photon fields.

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10. willia_A_Nelson on November 4, 2010 8:07 AM writes...

In vitro Biology is not In vivo Biology...and since this "breakthrough research" hails from England I would think their famous Bard would describe it as "Much ado about nothing".

Check the biomedical literature for all the "new" insights created (yes, created not discovered) from in vitro biology experiments using cultured Cells (Hela or otherwise) and you should realize (as PNAS obviously didn't) that this system in no way mirrors biology as we live it.

I haven't had a cold in 10 years since I learned to gargle with salt solutions as soon as I felt the onset of a cold coming on. But who wants to pay for testing this "remedy" in a Clinical Trial?

This TRIM21 fairytale should be ubiquinated and cast into the abysmal growing heap of experimental artifacts.

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11. Kismet on November 4, 2010 2:00 PM writes...

Here we go again with that canard...
just because you cannot patent or sell something with a good mark up, does not mean it will not be investigated. The literature begs to differ, e.g. zinc for the common cold (evidence mixed, may be useless); 'antioxidants' for everything (mostly failed) or currently vitamin D (work in progress, though, promising for influenza...), exercise, etc.

No patent - running studies becomes slightly more difficult NOT impossible.

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12. frequent visitor on November 5, 2010 5:54 AM writes...

@7 I agree with you...I think a delivery system would be needed in vivo, so this protein doesn't start hitting random Ab's Fc regions. I am not familiar with ubiquinated degradation pathways outside cells, so I think our bodies would recognize it as dead cells in the area. I am wondering how hard it would be to pair the amount TRIM that is actually delivered with the amount of Ab's our bodies produce.

A very important immunological discovery nonetheless.

But what would be strangely ironic is if upon administration, our bodies start raising Antibodies to tag between only 2're it, no you're it.

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13. krista on November 25, 2014 4:00 PM writes...

There must be criteria for an antibody to hang on to its antigen as it is internalized and criteria to traffic/trigger the innate immune pathway via TRIM21. Making antibodies with mutations in the Fc region where TRIM21 binds would be helpful to understand mechanisms. Viruses are really good at evading immune responses by making less important areas of their surface very attractive to antibodies. And virus proteins change shape as they enter cells which could cause some antibodies to fall off. Antibody responses are imperfect and so passive immunization can be a valuable treatment. Can't wait to see if we can make use of this.

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