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Grinding Up The Leaves and Roots

I’ve been meaning to write about this Stat profile of Jing-ke Weng at the Whitehead Institute, who’s searching for medicinally active compounds in exotic plants. That’s a field with a long and honorable history – some ferociously active compounds come from plant sources, and some terrific drugs have, too. But it’s been a while since one of those has showed up. Any guesses as to the most recent one? My own, off the top of my head, is Taxol/taxotere, which goes back nearly 50 years, and I think that arteminisin is almost exactly as old. Has there been anything since then? There have been whole companies founded on the idea of finding new natural products drugs (Shaman Pharmaceuticals, anyone?), but it’s been a very hard way to earn a living.

That’s partly because a lot of medicinally active substances have already been discovered, and you can spend a fair amount of your time discovering them again if you aren’t careful. And another big problem is that you can find some sort of plant extract that shows activity in an assay, but when you fractionate it, instead of one of the fractions turning out to have the Wonder Drug in it, none of the fractions actually have much activity at all. That one happens over and over, too, and is presumably due to polypharmacology of some sort.

One answer to this situation is to say “Forget your reductionist ways and embrace the whole plant extract”, but there are some problems with that. For one, the whole plant extract may well not be so active when dosed orally, as opposed to your cell or enzyme assay. For another, if you can’t narrow down to single active compounds, then does that mean that you have to go harvest the whole plant every time you want to treat people? The balance of active compounds in the extract can vary widely according to the season and growing conditions; polypharmacology can be a delicate balancing act. This can well mean that trying to farm the plant itself may not give you what you want, so you can face the problem of stripping it from the wild if that has to be the source. That situation is what looked like happening with taxol, and others, until a better synthetic source was found for the single active compound. But if there isn’t one, what then?

Weng’s group is looking for active compounds, because of just these problems, and I wish this effort good luck. No one can say that this idea is exhausted, and if something interesting comes out of it, odds are that it could be very interesting indeed. Modern analytical chemistry is a big help, of course, as is modern molecular biology (if you can get some more tractable organism to make the active stuff for you). It ain’t going to be easy, still. The Whitehead Institute, at any rate, is sufficiently hopeful, and I’m glad that someone is willing to put up the funds.

53 comments on “Grinding Up The Leaves and Roots”

  1. 404 file not found says:

    “Has there been anything since then?”

    There’s ET-743 (aka Trabectedin), approved for cancer in Europe, from a Caribbean tunicate. The isolation & structure determination were done by Ken Rinehart’s group in the ’80s. But Wikipedia says the activity was first noted in 1969, again about 50 years ago.

    Total synthesis by David Gin when he was a postdoc for Corey, but the commercial material is made by semisynthesis.

  2. Sideline Chemist says:

    Don’t forget Eribulin. Not the actual natural product, but derived from halichondrin B by the Kishi group and Eisai Research Institute in Andover, MA.

  3. Cannabidroid says:

    What about Epidiolex, Sativex and (potentially) everything else in GW’s pipeline?

  4. Curious Wavefunction says:

    Withania somnifera might be promising.

    http://www.pnas.org/content/109/9/3510.full

  5. Lane Simonian says:

    Artemisinin for malaria.

  6. Will says:

    ingenol mebutate also

    1. Erebus says:

      I was going to mention that one. It’s a rather recent discovery, and a very good example of a natural product drug.

      Ziconotide, from the marine snail conus magus, is another example. It was identified in the early 80’s, but its clinical utility was discovered later, and the FDA only approved it about 10 years ago.

      Speaking of marine natural products, I recall that there was a ton of interest in the Byrostatins as kinase inhibitors — but the fact that their production could never be scaled-up put the kibosh on that. How’s that for a rare and interesting situation?

      1. JAB says:

        I don’t think that bryostatin’s problem was supply (I led the effort that made 15 g of it) but rather lack of efficacy in the cancer clinical trials. Remember how potent this stuff is! I still hold out hope for bryologs, though they have been moving forward pretty slowly.

  7. Bagnar says:

    In my corridor, the team next to me is doing this kind of research. And a few weeks ago, we were discussing this very topic. Unfortunately, what you fairly described with these words “instead of one of the fractions turning out to have the Wonder Drug in it, none of the fractions actually have much activity at all.” happened to them.

    Fortunately, they are working with a combinaison of compounds. The main idea behind this is simple. We do not understand the mechanism of this very specific activity, but we see this combinaison of compounds is very potent.
    So they identified this combinaison of 7 or 8 compounds, which are quite similarsbtw, and work from it. Each of them is properly characterized.

    But, in the end, they have no activity for isolated compounds… Funny isn’t it ?
    Biology is a amazing science when it starts to determine mechanisms…

    1. Lane Simonian says:

      With a nod to Curious Wavefunction’s citation. Panax ginseng is another example in which the whole plant extract may be more effective than any of its components. Ferulic acid in panax ginseng appears to improve behavior in some forms of dementia including Alzheimer’s disease but may only slow the decline in cognition. On the other hand, several of the other components in panax ginseng may have a stronger affect on cognition but not improve behavior.

      http://www.ncbi.nlm.nih.gov/pubmed/21272180

      http://www.alzheimersanddementia.com/article/S1552-5260(10)01948-5/fulltext

      http://www.ncbi.nlm.nih.gov/pubmed/19298205

      http://www.ncbi.nlm.nih.gov/pubmed/22780999

    2. Scholander says:

      This is a well-known phenomenon in natural products circles. Organisms that produce active compounds make them via a pathway, and there’s rarely a defined endpoint of that pathway, because evolution. Instead, the biosynthetic enzymes are inefficient or vary in kinetics, there are multiple branches leading to multiple products. Taken together, there’s a synergistic effect that overwhelms the target (and prevents easy resistance to boot). The metaphor I used to describe it to the students in my class was that we want medicines to be a single bullet, fired from a sniper rifle. But nature is handing us shotguns. If we need more treatments (and we certainly do), we might have to learn to use the tools provided.

      1. A friend of mine who does research at a local Naturopathic college has told me that the FDA has the same mentality–it won’t approve a combination drug until its individual components have been approved. If the components have little activity toward the condition on their own, there seems to be no path to regulatory approval. If someone knows otherwise, please let me know and I can pass that along.

        1. PJK says:

          I believe Synercid (quinupristin/dalfopristin) might be an example: I don’t believe either (bacteriostatic) compound is approved independently, but the (bacteriocidal) combination is FDA approved at a 30/70 ratio.

          1. tangent says:

            Cool example in quinupristin/dalfopristin, and nice to see. I wonder if it was key to achieve the approval that somebody figured out why they’re synergistic. Understandable that FDA prefers to know a mechanism, but that’s going to be a real beast of a research problem for somebody even after they succeed in picking out some combo of five compounds as an active principle…

            I’d be fascinated to know — it’s a fuzzy question, but — how big the group of critically synergistic compounds is, across these situations.

        2. Leptopelis says:

          @Kyle
          I think it is the Naturopaths who have the exact opposite bias, against isolated single Natural Products. Certainly the FDA has approved mixtures in the past, Ivermectin being a prime example, as well as others mentioned in the comments.

        3. hn says:

          Is any real scientific research done at Naturopathic schools, such as would meet even this blog’s standards?

      2. tangent says:

        I’m curious, do you figure this phenomenon shows up pretty frequently while trying to isolate a natural compound — enough that it cuts significantly into the drugs you could otherwise discover? Or is it an unusual and remarkable occurrence?

  8. Bagger Vance says:

    Isn’t there something “problematic” with the way it’s almost always an Asian (or South-Asian)-named PI working on discovering things from traditional Asian medicine? I don’t know if it’s just too much overlap with woo (although I imagine the PR pieces write themselves), the idea that all the secrets of medicine will be solved by Orientalism/cultural appropriation, or whether this just seems biased against other ethnicities. Russian investigator looking at Russian folk remedies? Ho hum.

    1. Hap says:

      I suspect because medicine as a (sort of) science hadn’t been dominant there until recently? If people relied on various plant and animal extracts for treatment of diseases (because they didn’t have much else), then there’d be a lot of potential treatments for scientists to interrogate and maybe find something useful in. Being of the culture would help one figure out where to look, and might help with cooperation from people who still use the extracts. Medicine (I think) is more reliably curative, and once it becomes dominant, a lot of that knowledge would be practiced less and go away. Most of it might not be a loss (other than to the structure of the culture), but some of it might still be useful.

      1. Patrick Sweetman says:

        Europe used to have a rich culture of herbal medicine too, but a couple of centuries ago we burned most of the practitioners at the stake.

    2. Derek Freyberg says:

      That might be the case now, I don’t know, but there were certainly non-Asian researchers in the field in the past. Noble and Beer, at the University of Western Ontario, isolated vinblastine (Wikipedia) in the late 1950s; Morris Kupchan and his group at the University of Virginia were working on natural product anti-cancer agents in the 1970s; and I’m confident there are more recent examples.

    3. Curious Wavefunction says:

      I think it’s simply because medicine in the east has always had a more holistic component compared to that in the west: it’s philosophy was much closer to what we now call “personalized medicine” which recognizes that genetic variation entails recognizing different variants of even the same disease in different people. The key goal is to now apply a judicious combination of reductionist and emergent thinking to that knowledge and discover sound science and remedies.

      1. hn says:

        TCM has a huge body of pre/non-scientific literature that a researcher can dig through. The plants are systematically described and sourced. You can go to your local Chinatown and obtain samples. It’s very appealing, especially for we Asian scientists, to think that one can get lucky and find that magic molecule. But the TCM pharmacopeia has been combed over for a long time, including by Japanese researchers with modern technology and scientific practices, and relatively little has born fruit.

        1. cdsouthan says:

          hn’s remark “relatively little has born fruit” just about sums it up. So how many more decades of fruitless experimentation need to pass (and journal bombardments with – from what see as referee – dodgy articles) before THM (from C or anywhere else) is exposed as mainly placebo? Don’t get me wrong, there will be a few sucesses of finding novel bioactives from THMs, chemical biology will contunue to find more natural products with new and useful moas and more drug combiations will show clinical efficacy. However, if we look at the Ph I,II,II (Pharmaprojects Jan 16) figures of 1856, 2261, 954, not many have come out of the last decade of THM deconvolution.

    4. Isidore says:

      I think it may simply be a case of foreign-born US academics who have maintained contacts with former colleagues in their native countries. The foreign scientists have been carrying our research on local herbal medicines and other natural products and are happy to collaborate and supply materials to their US-based colleagues, as the later often have access to more state-of-the-art facilities and analytical instrumentation. I know of two such cases, one academic who was born and educated in China before coming to the US and another from Greece; both have had collaborations with colleagues back home involving obtained found natural products.

  9. partial agonist says:

    not a plant, but …

    Exenatide is a synthetic version of exendin-4, a hormone found in the saliva of the Gila monster that was first isolated by John Eng MD in 1992 while working at the Veterans Administration Medical Center in the Bronx, New York.

  10. A Nonny Mouse says:

    How about theobromine for persistent cough? Sold in South Korea, I believe, and still being developed for EU/USA. Could just eat a lot of dark chocolate.

  11. Bernard Munos says:

    Crofelemer approved in 2012 for diarrhea. Also spinosad approved in 2011 for head lice.

    1. Rastafarian says:

      Fun fact on the discovery of spinosad – discovered at Lilly in 1985 when they still did natural products research. Isolated from soil collected at a rum still in Jamaica, International Journal of Systematic Bacteriology 40 (1): 34–39.

  12. Anonymous says:

    How many times people go through the trouble of identifying the right fraction that has the activity (from plant/marine organisms/soil bacteria/…) only to realize that they have re-identified a known natural product? As an outsider, it feels that this will be a big problem. Even if you are lucky enough to identify the fraction with the desirable biological activity, isolating the pure compound and determining it’s structure will still be enormously time and resource consuming.

    A group from UCSD has started a company (http://www.linnaeusbio.com/) to generate fingerprints from multidimensional cytological profiling to rapidly identify small molecules with biological functions not seen before. This will not help with the ‘polypharmacology’ issues but will at least help you avoid rediscovering known natural products assuming you have the profile of the known natural products. They are applying this technique for the discovery of novel antibiotics but it has the potential to more broadly revitalize natural product isolation for many other disease areas (at least in theory!).

    1. onceachemist says:

      I think MS-MS would be a simpler fingerprint to check active fractions vs knowns?

      1. anon electrochemist says:

        You’d be surprised how hard building an MS-MS library is. MS-MS data is not systematically reported in any fashion, the vast majority of the compounds are not available as standards, and even with good LC, you often co-elute isomers. Older data is complete garbage, and people still don’t report collision energies, etc. Spent a couple years on this.

        Even when you can separate with HPLC, structural assignment is often impossible because of rich stereochemistry in natural products. As an example, anything with a sugar on it yields isobaric garbage that can’t be differentiated.

    2. hn says:

      This is called dereplication. Yes, rediscovering known compounds is a major bottleneck in the field. There are probably many interesting undiscovered compounds in nature, but perhaps we’ve already done a thorough job of picking the low hanging fruit.

  13. A nonny mouse says:

    What about veregen? It literally is green tea extract to treat HPV

  14. EY says:

    galantamine

  15. Druid says:

    I had the same problem in my PhD on a termite repellent oil, separated by prep-GC. Collect everything, it worked. Collect it as 2 halves – neither worked. But I had fun characterizing all those sesquiterpenes.
    As for traditional medicines, 3 patients go to the healer (who can only treat the symptoms, really – no reliable diagnosis) and pay for the medicine. 1 gets better and sings the praises of the wise healer. 1 person does not get better – because he has been cursed – can’t fix that. The third patient gets such bad D&V that he does not dare complain about the healer in case he gets given something stronger. A bit like chemotherapy, And maybe better than some approved drugs …
    There are natural product medicines out there, but can you get them to work safely in umpteen double-blind randomized clinical trials? How do you double-blind green tea?

    1. Morten G says:

      And you got activity back when you combined the two fractions?

      1. Druid says:

        Sort of. Actually I made a single prep of the whole run and that was active. It was theoretically possible that there was a minuscule incredibly potent active in the few seconds at changeover between the 2 fractions, but I was never going to identify that anyway! It was possibly because the termites in a colony are not as identical as they appear; often, 1 in 10 were less sensitive to the effect and could overcome it. This is probably the same situation in disease. Cell lines in the lab may behave consistently, but some diseased cells in the patient may be less sensitive to the drug.

        I liked the tramadol crack – it’s a controlled substance in the UK, so someone must like it.
        I have also been impressed by the nominations of drugs derived from natural products, but in most cases it took as long or longer to get approval for any of them as for any purely synthetic drug, and they have just as many side-effects. Natural products are not an easier route to new medicines.

  16. Ted says:

    Tramadol, right?

    just kidding…

    -t

  17. Natural says:

    I work in a lab where we do this every day. It is actually rare that I find the activity is from many different fractions that need to be combined for activity. It usually resolves to one most potent compound or a family of structurally related compounds. Thankfully so, it would drive me nuts if it was the other way around.

  18. Kaleberg says:

    Chinese “traditional medicine” as we know it was more or less invented by Mao back in the 1950s to provide health care for the under-served given there were few properly trained doctors and no pharmaceutical industry to speak of. Mao himself and his personal doctors recognized that Chinese traditional medicine was bunk, but had to provide some sort of medical care for political reasons.

    1. HT says:

      Are you merely being satirical? TCM, like the use of herbal medicine elsewhere, goes back a long way.

      1. lurker says:

        Traditional, Chinese, medicine, like traditional medicine elsewhere, has existed since prehistory. “Traditional Chinese Medicine” as currently practiced is a distilled version of _some_ traditional precepts which was standardized under Mao and institutionalized by the state for political reasons. See e.g. Taylor’s Chinese Medicine in Early Communist China, 1945-1963.

      2. Nick K says:

        TCM goes back a long way. So does witch-doctoring. The only valuable contributions TCM has given the world that I can think of are artemisin and ephedrine (Ma Huang).

        1. hn says:

          Some other drugs with TCM ties are camptothecin, omacetaxine, and arsenic trioxide.

  19. milkshake says:

    Motherboard has interview with Fenical from Scripps Oceanographic Institution. Apparently they have quite a few good compounds, but the only interest they get is for anti-cancer compounds, not for MRSA – effective antibiotics. The structure of their anthracimycin looks quite nifty small polyketide, and it seems promising in mice.

    https://www.youtube.com/watch?v=pUt4ArplGnM

  20. eugene says:

    Isn’t this stuff the business model of the Xenobe Research Institute?

    (gets his coat…)

  21. Druid says:

    Good point about antibiotics. Without natural products we would still have sepsis wards. Unfortunately the economic model has not supported antibiotic R&D for over 30 years, in spite of all the hand-wringing. Fix that and I will start digging.

  22. Dr. Manhattan says:

    @milkshake”Apparently they have quite a few good compounds, but the only interest they get is for anti-cancer compounds, not for MRSA – effective antibiotics. ”

    Right now, we have several effective antibiotics for MRSA. beginning with the old standby vancomycin, there is also daptomycin (Cubicin), linezolid (Zyvox), torezolid (Sivextro), televancin (Vibativ), oritavancin (Orbactiv), ceftaroline (Teflaro) and possibly ceftobirpole at some point. These work by several distinct mechanisms, so resistance is not a big issue at present. Yes there are still MRSA deaths, but these are often in very sick, hospitalized patients, often immunosuppressed, that acquire the organisms in the hospital. And the hospital MRSA strains tend to have more resistance determinants and be more aggressive. Not surprising that there is lukewarm interest in yet another MRSA compound. As is well known in the antibiotic field, the real need si for new Gram negative compounds.

  23. hn says:

    I don’t get this article. Sounds like a biologist just discovered the field of natural products chemistry?

  24. D says:

    Carfilzomib (Kyprolis) is based on epoxomicin (found in Actinomycetes) and was developed by Proteolix (acquired by Onyx in 2009, then by Amgen in 2013). It was approved by the FDA in 2012.

  25. mike says:

    Caspofungin

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