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The Weirdness of Ebselen

I think that most medicinal chemists look at the structure of ebselen and say “That’s not a drug”. Selenium atoms don’t belong in drugs, we figure, and Se-N bonds most certainly don’t. But it stands as a rebuke to our intuitions, because it’s been kicking around in the clinic for some time (and has certainly looked more interesting there than a lot of stuff that I’ve worked on over the years).

One recent application has been treatment of Clostridium infection. In 2015 it was reported that ebselen could be an antivirulence agent, and a mechanism was proposed where it affected the cysteine protease activity in the autoprocessing of the Toxin B virulence factor. That’s quite plausible, because (as you might well expect) ebselen is known for hitting Cys residues and inactivating them, which accounts for the weird variety of conditions and targets it’s been studied against over the years. The screen was for autoprocessing inhibitors, and ebselen bubbled to the top quickly.

Now comes word that further study has made things a bit more complicated. This new work took advantage of a Toxin B construct that had all of its Cys residues mutated, and you would expect ebselen to be pretty much useless in that situation. But it was equipotent versus wild-type and “de-Cys-ified” protein, which takes care of that theory. Moving to another domain of Toxin B, though, it appears that ebselen may be doing its work on the toxin’s glucosyltransferase activity. The human target of that activity is a GTPase protein called Rac1, and ebselen covalently modifies its three cysteines, which makes it no longer a substrate.

So far, so good: but the 2015 paper had specifically reported that ebselen didn’t have an effect on the glucosyltransferase function. The authors dug down into the details:

To reconcile these conflicting findings, we evaluated all aspects of the two studies to find any differences between our methodologies that might account for the discrepancies in our results. The answer turned out to be that the reducing agent dithiothreitol (DTT), which removes ebselen from Cys side chains, was included by Bender et al. in their assay of GTD activity, but not in their assay of APD activity (1). To demonstrate this, we tested inhibition of APD by ebselen in the absence and presence of DTT and saw that inclusion of DTT completely abrogated inhibition by ebselen (Fig. 1G). Similarly, addition of DTT to ebselen-labeled Rac1 relieved the inhibition of GTD activity (fig. S1). Thus, in the absence of DTT, ebselen can covalently inhibit both the APD and the GTD; however, as outlined above, on the basis of its ability to protect cells from intoxication by wild-type and Cys-less TcdB equally, it is not the APD inhibition that is responsible for the protective effects of ebselen.

There you go – if your mechanism of action depends on messing with Cys residues, the temptation is to make sure that you’ve added DTT to ensure that they’re all reduced and ready, but in this case, that same reagent is also wiping out the effects of the compound under study. This would seem to nail down ebselen’s activity against C. dificile toxin, but given the way that it hits proteins from every direction, it’s going to be hard to say when this story is over.

As everyone who’s worked on the compound knows, that also complicates its potential clinical development. Ebselen has been in clinical trials for stroke, and it’s being looked at now for bipolar disorder, suggested for use against osteoporosis, as an antifungal, and many more applications. Normally, one would get a bad feeling about a compound that seems to hit so many things (witness the curcumin story from the other day), but ebselen appears to be more real, although still a very hard candidate to develop. We’ll see if it ever finds a home!

51 comments on “The Weirdness of Ebselen”

  1. David Borhani says:

    Why no chemical structures anymore?

    1. Derek Lowe says:

      Putting one in now – I didn’t have time this morning!

  2. Jano says:

    Derek – the link to the new report is broken….

  3. Farma Fred says:

    Nice to see academics caring about important issues like these. Well done!

  4. petros says:

    Quite a bit of research was done with this at the Wonder Drug factory in Germany not long after it was first described (in 1984)

  5. local softness says:

    As found with the case of benzoisothiazolones, one would expect ebselen to be even more reactive (promiscuous) towards cysteines. You should also include Zn fingers (whether host or pathogen) as potentially disrupted by ebselen, particularly where the cysteine coordination number of Zn is greater than 2. In biochemical assays involving compounds like this, the exp redox conditions can definitely introduce artifacts – research involving the discovery of cysteine protease inhibitors has lots of discussion/examples.

  6. Passerby says:

    The ebselen story demonstrates that the current paradigm of target-based drug discovery is but the tip of the iceberg. There are tons of weird-looking, “selectively non-selective” compounds out there that could function as viable drugs, which could be almost impossible to discover via target-based approaches.

  7. anonymous says:

    What’s next? How about the Telluride analog of the same? Hmm..future direction.

  8. Lane Simonian says:

    And I cannot help but add ebselen for Alzheimer’s disease.

    https://www.ncbi.nlm.nih.gov/pubmed/24160297

    Here is the key for Alzheimer’s disease and likely a variety of other diseases as well.

    “The inflammatory mediator peroxynitrite, when generated in excess, may damage cells by oxidizing and nitrating cellular components. Defense against this reactive species may be at the level of prevention of the formation of peroxynitrite, at the level of interception, or at the level of repair of damage caused by peroxynitrite. Several selenocompounds serve this purpose and include selenoproteins such as glutathione peroxidase (GPx), selenoprotein P and thioredoxin reductase, or low-molecular-weight substances such as ebselen. Further, flavonoids, such as (-)-epicatechin, which occurs in green tea or cocoa as monomer or in the form of oligomers, can contribute to cellular defense against peroxynitrite.”

    The next step is finding a combination of antioxidants that are more effective than ebselen and curcumin. One set can be found in Korean red ginseng and heat processed ginseng (Korean red ginseng steamed at higher temperatures).

    Evaluation of the peroxynitrite scavenging activity of heat-processed ginseng.

    “To ascertain the principal active peroxynitrite (ONOO(-)) scavenging components of heat-processed Panax ginseng C.A. Meyer (sun ginseng [SG]), the ONOO(-) scavenging activities of fractions and components of SG were compared. The results demonstrated that the ONOO(-) scavenging ability of SG was due to its ether fraction containing phenolic compounds. High-performance liquid chromatography analysis and ONOO(-) scavenging activity tests of the phenolic acids contained in SG identified vanillic acid, ferulic acid, p-coumaric acid, syringic acid, and maltol as the main active ONOO(-) scavenging components of SG. The ONOO(-) scavenging activities of phenolic acids and maltol were dependent on the degrees of their proton donating ability.”

    “Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer’s disease.”

    “Improvement of Cognitive Deficit in Alzheimer’s Disease Patients by Long Term Treatment with Korean Red Ginseng”

    It is deceptively simple, find compounds that are excellent hydrogen donors and you effectively treat Alzheimer’s disease (and perhaps other disease as well).

    1. Anon says:

      Jesus, give it a rest will you.

      I’d rather let the spambots in than listen to you harp on and on and on about peroxynitrites, regardless of the topic.

      Get your own blog.

      @Derek: Any case you can add a filter?

      1. Phil says:

        Look on the bright side: at least we have a solution to South Park’s Underpants Gnomes equation:

        1) Steal underpants
        2) peroxynitrites
        3) Profit

        1. Jewels says:

          Thanks Phil. Always wanted to spray milk all over my phone at 3am after trying to drink it then laugh silently.

      2. Lane Simonian says:

        I personally am not a fan of censorship unless someone says something very hateful or ugly. And even in that case maybe that person should still be heard if only to remind us that such people still exist and to offer a rebuke. I appreciate moderators who keep censorship to a minimum even when they may strongly disagree with what is being said.

        I try to provide a different set of relevant information each time even though there is some repetition of studies. The hope is to spark some interest in the hypothesis and the considerable weight of evidence behind it rather than to simply perturb people. Through this process, I have sometimes been pointed to very critical information that has helped me see things more clearly and more correctly.

        I try not to respond to even very harsh criticism at all any more and when I do I try to be civil.

        1. Unemployed MS says:

          Dear Lane,

          I just tried a quick google search of your name, to see what pops up. I’m doing this because you say that you want to spread the word of peroxynitrites and generate discussion and hypotheses, It seems the only hits I can easily find (if you are the Lane Simonian of Western Nevada College, the history professor) are a smattering of comments here and there. I looked at alzforum dot org, which has the tagline of “Networking for a cure”, and yet your last comment there was in 2011.

          I agree with whoever said, why not start your own blog. You obviously have lots of thoughts on the matter, and it might help your cause to have more comprehensive, long form discussions with citations (rather than short comments on a chemistry blog), as well as giving you a dedicated place to share your thoughts.

          Indeed, why haven’t you started one?

          1. Lane Simonian says:

            I am a contributor to Seeking Alpha regarding Alzheimer’s drug trials. My primary focus, however, is writing on Alzconnected which is one of the largest sites for caregivers and people with dementia. One can find hundreds of citations and discussions about the possible causes and treatments of Alzheimer’s disease there and certainly not just by me.

            I read each day this blog and other blogs that often discuss medicinal biology and chemistry. I usually just read rather than comment. I also read each day as much of the current news on Alzheimer’s disease as possible and will comment when I feel another perspective outside of the mainstream (i.e. amyloid is the cause of Alzheimer’s disease) is warranted.

            I am a history instructor but my background is in Latin American environmental history–which entails also a background in biology and environmental sciences. That usually means that people think I am unqualified to discuss Alzheimer’s disease (including it would appear the more recent editors at Alzforum), but that is partially a misjudgment.

      3. Dionysius Rex says:

        Anon 1.55pm – you disregard the hypothesis because Pharma has been so successful in the Alzheimers arena? Maybe some more open minded thinking is called for! (whether it’s peroxynitrites, infectious agents, or spiders from Mars) – a little less hubris might be warranted.

        1. Anon says:

          It’s not so much an issue of hubris than repetition. I get it, peroxynitrites could be the answer. But Spiders from Mars would be a breath of fresh air, tell me more!

  9. Magrinho says:

    The Simonian Corrolary to Godwin’s Law… Sigh

  10. MoBio says:

    We see it as a ‘frequent hitter’…PubChem lists ‘active’ in >350 assays.

    It’s a promiscuously active compound!

    1. Derek Lowe says:

      Yeah, I’m on the fence about this one. I tend to think that curcumin is probably not going to be anything useful, whereas this just might, but I’m having trouble quantifying my biases (!)

      1. Gordonjcp says:

        > I tend to think that curcumin is probably not going to be anything useful

        It makes curry pretty tasty.

        1. eyesoars says:

          It makes tasty curry pretty!

  11. Belgian Grad student says:

    Check out Auranofin, basically the same story as Ebselen. Clinically used drug that hits many targets presumably through reactivity with Cysteines. Has been described as having potential for treating many different ilnesses and shown activity against both viral and bacterial infections.
    In my opinion Auranofin and Ebselen are both Pan-Assay Interference Compounds (PAINs) which is essentially proven by checking their bioassay activity in PubChem like MoBio has already mentioned in the comments.
    I think we would be surprised if we knew how many clinically used drugs are hitting multiple targets and would not have been developed given the current practices of drug design/discovery.
    How much is our black swan-driven way of doing drug development linked to the so-called Eroom’s law?

    1. anon electrochemist says:

      I thought I had seen weird structures, but Auranofin made me sit back in my chair and rethink how this field works.

    2. Rad says:

      disulfiram as well

    3. tangent says:

      In a way it’s encouraging how much pharmacological space is left to explore: the combinatorial explosion of modulating multiple targets in a deliberate manner.

    4. Jonathan Kil says:

      Hi Derek,

      The Daichii ebselen stroke trials were probably the most advanced clinically, but were limited due to the sample size, the nature of that disease, and the approval of tPA in 1997. In addition, I thought you maybe interested in our ongoing clinical trials in sensorineural hearing loss and tinnitus with SPI-1005. We have completed a Phase 1 and Phase 2 in acute noise induced hearing loss which were highly successful. We are currently enrolling a Phase 1/2 in Meniere’s disease (hearing loss, tinnitus and vertigo) and preparing to enroll two ototoxicity studies involving chemotherapy or antibiotic receiving patients. In several different models of acute neurotologic injury, we and others have shown that ebselen is highly otoprotective through its action as a GPx1 mimic and inducer. This later effect is somewhat dependent upon Nrf2 activation. My feeling is that ebselen will find a home in diseases where decreases in GPx activity result in the establishment of acute injury and the progression to chronic disease and/or in specific organs where GPx is the dominant catalytic antioxidant enzyme such as the inner ear, retina, lung and some areas of the forebrain.

      1. Al Dune says:

        Hi Jonathan,

        I have struggled with tinnitus since leaving the USMC in 1988. Then, in 2009, a pneumatic nail gun discharged by my right ear, giving me 100% NIHL (noise induced hearing loss) in my right ear. The ear drum is undamaged. What are some clinical trials, resources or other contacts would you suggest regarding my conditions? I would love to participate in any study, trial or safe drugs which might reverse or improve my condition.

        Thank you,

        Al

  12. Barry says:

    if Paul Ehrlich and Alfred Bertheim had been burdened with all our modern sophistication, they would never have found arsphenamine/salvarsan

    1. Design Monkey says:

      They weren’t. T’was brave new world, where one could sell heroin OTC with claims, that it is not addictive, and make medicinal elixirs with diethylene glycol.

  13. LiqC says:

    If the pharmacology of a vicious Michael acceptor dimethyl fumarate is tractable, then ebselen should not be that much trouble…

  14. gippgig says:

    How about the sulfur analog? (Anyone for livermorium?)

  15. gippgig says:

    …and how about the selenoxide and seleno, er, what is the seleno analog of a sulfone called? Wait a minute, how about the selenosulfide (is that what it’s called?)?
    …and to go further afield, anyone look at the seleno analog of sulfa drugs? Penicillin? …this is getting complicated.

    1. sjb2812 says:

      RSe(=O)2R’ is a selenone, I think

      1. sjb2812 says:

        Or did you mean e.g. RSe(=S)(=O)R’..etc

  16. Jewels says:

    Me, I’m just waiting for the miracle pain drug, thanks.

    After all, if Oxy worked for headaches, I wouldn’t be reading a bloody chemistry blog at nigh 4am. No offense Derek. I love your blog and have shared the crap of of it, starting – where else – with “Sand won’t save you this time”. And I’m actually reading “Ignition” right now too. Thank you guys, the lot of you, for recommending it. But I’d *still* bloody well rather be asleep than awake reading your blog because I’m in too much pain to sleep!

    P. S. Anyone who’s tried d/l’ing “Ignition” and can’t get the PDF to come out right. Get FBReader (best ebook app!), and it’s PDF attachment from the Play Store. Then open it and open Ignition. Voila!

    1. Jewels says:

      “Its PDF”, not “it’s”. And yes, it does matter – at least to me!

  17. Anonymous Researcher snaw says:

    Promiscuous Simonian Inducers?

  18. JBstein says:

    spiders from mars acting on multiple tagets is fine with me, as long as they have no safety issue. that’s were i see some fog coming up. selectivity has a up-side when it comes to safety once in a while; but hey, that is probably just modern sophitication!

  19. Unemployed MS says:

    Back to the topic at hand, can anyone with more knowledge shed some light on how potential development of this compound will be affected by patents? I’m asking because it looks like it’ been around for quite some time, as they were doing stroke studies of it published back in 1998. Will anyone be able to get the exclusivity needed to get this to market?

  20. Ida Bruurs says:

    Give it to the people with bipolar disorder, they have suffered long enough, and even double, from the disorder itself, and from the side effects of 60 year old lithium, also a weird drug of which we still don’t know exactly how it works. Give PEOPLE a chance, we have nothing to lose anymore, except our lives. Thank you.

  21. Zemyla says:

    Why wouldn’t there be drugs with selenium in them? It’s useful enough in the body that it has a specific amino acid for carrying it, so selenium-bearing drugs seem only slightly more unusual to me than sulfur-bearing ones (which you see all over).

  22. Ebselen says:

    Well, get ready because things are about to get even more weird and complicated. We are going to be pulling out a protein which you guys never even mention.

    This is the highest affinity target we have ever seen for Ebselen.

    1. Matt says:

      Can you elaborate on this? I am currently building models for how Ebselen may work for certain neurodegenerative disorders, and if Ebselen interacts with proteins not named cysteine this could really add to these models…

  23. Angela says:

    I have been tracking development of this drug since 2013, and am wondering when may this drug reach a point that there are clinical trials in the US for adolescents? Also if clinical trials go well, when is the earliest that this drug will be commercially available through a US or Canadian pharmacy?

  24. Deb Falcon says:

    Selenium toxicity can occur with acute or chronic ingestion of excess selenium. Symptoms of selenium toxicity include nausea; vomiting; nail discoloration, brittleness, and loss; hair loss; fatigue; irritability; and foul breath odor (often described as “garlic breath”).

    So we are studying yet another poison to put in our bodies that ends up causing more side effects, which makes you wonder what is worse, the illness or the side effects and poison to our bodies?? (Husband with bipolar illness for several years, on lithium, stage 3 kidney disease)

  25. David Edwards says:

    Took a peek at auranofin mentioned above … now that is a seriously weird molecule. I don’t think I have ever seen a molecule with a S-Au-P sequence of bonded atoms before! Ebselen looks almost normal in comparison to THAT …

    I sense a competition looming … who can devise the strangest sequence of bonded atoms in a molecule that makes it to at least Phase 1 clinical trials?

    1. Barry says:

      Well, if it’s in the U.S. pharmacopeia, there’s a credible argument for keeping in the HTS screening deck. But many med. chemists would deem that–even if it hit in the assay of the day–there’s no path forward “from Hit to Lead” for a heavy-metal drug for further drug discovery.

      1. David Edwards says:

        The competition I proposed above, is, of course, still open to those med chemists lacking the reservations you cite. 🙂

        Though, for fairly obvious reasons, I suspect some non-heavy metal elements will still not feature in said competition, should it ever be launched seriously. Beryllium is one element I suspect won’t have pharmaceutical applications any time soon (and Derek will probably have a fit at the thought this ever happening, I suspect!). For entirely different reasons, I suspect Gallium will also be an unlikely choice, unless anyone out there knows something I don’t, which in this company is always a possibility.

        After Derek’s piece on dimethylcadmium, I suspect cadmium will be out of the running too, unless someone alights upon a very exotic use for it that doesn’t involve the production of toxic metabolites Arclighting your liver and kidneys. Likewise, given the less than happy outcomes arising from some people’s mistaken attachment to silver as a prophylactic, that one might be given a wide berth too.

        But, if research leads to a wacky combination of element being found to be useful therapeutically, I’ll celebrate the result, whilst at the same time musing on what strange lessons such a development will be teaching us all about the interface between biology and chemistry.

        I suspect Derek might like to reserve some space to catalogue the truly unusual candidates for the competition, on the basis that someone will provide him with the requisite blog fodder, and even more head scratching at the reasoning behind the resulting weird molecule. Analgesic with an Ru-Ta bond, anyone? (If that ever comes to pass after me suggesting it, no one will be more surprised than myself, I assure you!).

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