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Natural Products Drug Discovery Wins a Nobel

This year’s Physiology/Medicine Nobel has gone to three discoverers of important drugs for topical diseases: William C. Campbell and Satoshi Ōmura for Avermectin, and Youyou Tu for Artemisinin.

I last wrote about artemisinin here, with reference to a scale-up synthesis. And scale-up is a useful topic with that one, because it’s one of the most useful antimalarial drugs in the world, and has led to a number of useful derivatives as well. Tu was in charge of a screening and drug discovery effort in China in the late 1960s, and while the discovery of this compound would be a remarkable accomplishment under any conditions, it’s especially so considering that China was in the middle of Mao’s destructive (and profoundly anti-intellectual) Cultural Revolution. Over the years, I’ve worked with several Chinese colleagues who had been sent out to work in the fields during this period, losing  what could have been some of their most productive years.

Tu worked from ancient Chinese texts, looking for descriptions of preparations that might have been used against fever or the other symptoms of malaria. One described an extract of an Artemisia species as good for “intermittent fevers”, which sounded promising, and once a modern extraction technique was worked out, there was indeed a very active (and very unusual) compound in there. Artemisinin, famously (among chemists, anyway) has an endoperoxide ring in its structure, a feature you don’t see much, and that’s essential for its activity. Derivatives of it continue to be investigated, as well as other endoperoxide-containing compounds. (Update: I should note that one of these derivatives, artemether, is part of the combination therapy Coartem, manufactured by Novartis, who have reduced its price substantially over the years, and who provide it at no profit to many international efforts). This discovery advanced the whole field of antimalarial research hugely, and has surely saved millions of lives.

It’s worth remembering, too, that there were a lot of other ancient texts that described things that might have worked, but which had no effect at all. Folk and traditional medicine has been the source of many good drug leads, but it’s also been the source of a lot of useless placebos (or worse). Finding such an immediately useful drug in such a pile of false leads was really remarkable.

As for avermectin, I go back a ways with that compound as well, since I had close friends in graduate school who were working on a synthetic route to it. It’s a complex and tricky structure, especially the “southern” part of the macrocycle, which is quite labile and has tripped up many a synthetic chemist in this area. The organism producing it (and related compounds) was discovered by Ōmura and colleagues in Japan, and sent to Merck in 1974. Campbell and colleagues were able to ferment it on a larger scale, and isolated the whole family of natural products, which had remarkable activity against a variety of pests. (Here’s a recent history by Campbell himself).

Many derivatives of these structures were prepared as well. If you saturate the double bond in the spiroketal part of the parent avermectins, you get into the Ivermectins, which have also been tremendously useful in both veterinary and human applications. Both classes of compounds show up as deworming agents, flea and tick killers, agents against mites and lice, and more. Merck also dedicated itself to donating as much Ivermectin as needed, for as long as needed, to treat river blindness in West Africa. Hundreds of thousands of children in these areas have been spared the effects of the disease thanks to this, and combining this treatment with a spraying program has protected millions more (as well as opening up a large amount of once-dangerous arable land).

And just as with artemisinin, it’s worth remembering the number of organisms screened by the Japanese team, and the number of things tried at Merck before finding these. Natural products drug discovery can be amazing when it works, but you don’t just waltz into the field and find a wonder drug. Vast amounts of time, effort, and money have to go in for it to have a chance. Congratulations, then, to Ōmura, Campbell, and Tu for their contributions to science and to human life, and for winning today’s Nobel!

26 comments on “Natural Products Drug Discovery Wins a Nobel”

  1. I think this discovery makes as good a case as any for subjecting traditional Asian medicine to rigorous scrutiny. As you said, most of the results might be useless, but the one that are not could be priceless.

    I wonder how the conformational transition of the six-membered ring from avermectin —> ivermectin play into the biological activity of the molecules.

  2. Bernard Munos says:

    I think praise and thanks should also go to the Medicine for Malaria Venture and Novartis whose collaboration played a critical role in developing artemisinin, and turning it into the drug Coartem. It is worth pointing out that Novartis offers Coartem at cost with no profit to public health institutions, and has delivered more than 600 million treatments for adults and children in the last decade. It also funds the Novartis Institute for Tropical Diseases in Singapore, whose mission is to pursue research and drug development for neglected diseases. Worth remembering at a time when many companies have backed out of such research. The industry is not just a bunch of blood suckers — even though they are more common these days. There remains companies who take their ethical responsibilities seriously. While they may not always get everything right, 600 million people are glad they exist.

  3. Derek Lowe says:

    Thanks, Bernard! I’ve updated the post accordingly.

  4. Chemjobber says:

    A favorite aspect of the artemsinin discovery story is from this NYT article from 2012:

    “Also, after rereading a manuscript by Ge Hong, a fourth-century healer, prescribing qinghao steeped in cold water for fever, she realized that boiling, the typical extraction method, was destroying the active ingredient. She switched to ether, and qinghao became the first plant extract 100 percent effective at killing malaria in mice.”

    1. Phil says:

      Nice link CJ. The line right after is noteworthy:

      “And before human testing began, Dr. Tu said, she and two colleagues took it themselves to make sure it was not toxic.”

      That might have made the Nobel winnowing even easier…

  5. hn says:

    Nobel Prize-winner Satoshi Omura has revealed that the key to developing ivermectin was found on a golf course.

    Omura and William Campbell on Monday were announced as winners of the Nobel Prize in medicine for developing the drug that has helped lower the incidence of river blindness and lymphatic filariasis, two diseases caused by parasitic worms.

    Omura said the key substance was taken from a microbe contained in the soil sample at a golf course near Tokyo. He says he always carries a plastic bag in his wallet so he can collect soil sample any time.

    Asked if he likes to play golf, he grinned, and said “yes.”

  6. Chris says:

    @Ash, from memory I don’t think the reduction of the double bond has much effect of biological activity. However hydration of the bond via the ring opened spiroacetal ketone is a facile process and it may be that hydrogenation is an way to avoid this.

    1. Anonymous says:

      @Chris. Whith due respect, you are in error. Jack Chabala at Merck was instrumental at developing methodology for reduction of the conjugate double bond using Wilkinson’s catalyst. I was his charge that investigated this method and gave Sir Wilikinson visibility on how useful this catalyst was. The whole thing revolved about using ethanol as the solvent. The rest is history,

      1. Anonymous says:

        My apologies, Chris – I had a brain freeze from another Chris Swain from SP of yore. I knew Nadia from NK-1 and we used in Rahway your leads for BBR3. Those were happy, literally, guinea pigs.

  7. Chris Swain says:

    @ Anon. Interesting so did it have a significant effect on intrinsic biological activity or on stability?

  8. Chris Swain says:

    Apologies if this appears twice.

    @Anonymous. Interesting but did it have an impact on the in vitro activity or did it improve stability?

    1. Anonymous says:

      Merck wanted to use Avermectin as an insecticide for ornamentals. Unfortunately, it did not degrade well once applied and resulted in untoward toxicity in runoff streams that seriously affected fish and indigenous life in streams and rivers. Ivermectin was the cat’s meow in that it was substantially less toxic (100- 1000 fold less toxic towards invertebrates). The EPA negative issues and value added (monetarily and politically -Vagellos /President Carter) advantages of Ivermectin, plus patent and outsourcing issues precluded further research efforts at Merck.
      PS Your former lab, which is probably in the plumbing section and Derek’s, which is in lighting at Home Depot site in Bloomfield would be a good place for a reunion. I’ll ask Jim Doherty to bring the Guiness.

  9. Andy II says:

    @Chris: Take a look at this. Nobel society provides a very useful reading with key reference.
    Looks like avermectins were base compounds discovered by the Omura team and the Merck team led by Campbell characterized the biological activities of avermectins and produced a drugable analogue (broader activity and less toxic to human), Ivermectins thru med chem (selective hydrogenation).

  10. Nick K says:

    Wonderful to see this work acknowledged finally, and makes a refreshing change from the usual Chemical Biology stuff which normally wins Nobels these days.

  11. crni says:

    Hehe, I read the “topical diseases” and read the whole paragraph expecting the Head&Shoulders team to win it 🙂

  12. A Nonny Mouse says:

    It should be noted that the Novartis institute has also made a significant malaria breakthrough with NITD609 which cures with a single dose in a unique manner- a pig to make, though (having done it!).

  13. lynn says:

    Particularly nice to note that Campbell identified avermectin [in an apparently unfractionated fermentation broth] as an antiparasitic by screening for killing parasites in mice. Ultimate phenotypic screen!

  14. cytirps says:

    Mainland China media coined You You Tu as “three does not”. She does not have a PhD degree, she does not study overseas and she is not a member of the Academy of Science. She reminded me of GB Elion who shared the Nobel Prize in Physiology or Medicine in 1988. She had only a MSc degree from NYU but never a PhD degree.

  15. Soon-to-be-former BMS person MOLS says:

    When BMS, like the rest of Big Pharma, got out of Microbiology and Natural Products I thought they were making a mistake. I still think so. Kudos to these Nobelists.

    Unfortunately, resistance to artemisinin is becoming a major concern, so the world badly needs more research to find new drugs that will be as effective as artemisinin when resistance has become common in more countries (at present, resistance to artemisinin is only a serious matter in a few countries).

    On a related note, I love what Jimmy Carter said in a recent interview about his cancer diagnosis: ‘I would like the last Guinea worm to die before I do.’ Carter got interested in Guinea Worm about 30 years ago after a conversation with an African health expert. He told Carter that although guinea worm had an enormous impact on millions of people, nobody was funding work on it because it rarely killed its victims. It did make them miserable and unable to work for many weeks, which had a huge impact on their lives, their families, and their countries. So Carter decided to make it a priority for his organization. Thirty years later, the job is almost done.

  16. XUEWU LIU says:

    In this year’s news release of the Nobel prize in physiology or medicine. I found you think Tu found artemisinin comes from the idea of traditional medical literature China. In fact, in traditional Chinese medical literature, only recorded the Artemisia carvifolia with anti malaria effect, and no records of Artemisia annua with antimalarial efficacy.
    Artemisinin is a substance extracted from Artemisia annua. In China words, artemisinin is “Qing-Hao-Su”, literally seems to be derived from Artemisia carvifolia. This is some of the traditional medicine of the maintenance of the speculation, this speculation in order to promote Chinese traditional medicine, the name of the majority of Chinese people believe that artemisinin directly from Chinese traditional Chinese medicine(Artemisia carvifolia), the drug discovery is the contribution of Chinese traditional medicine. Unfortunately, the English literature continues this way, leading to the Nobel committee also produce the same misunderstanding.

  17. John says:

    Seems Nobel Laureate William Heck (of the Heck reaction died.)

    No one noticed?

  18. David says:

    To paraphrase Futurama,
    “I knew it! Traditional medicine: 1, modern medicine: 1,000,000,000.”

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