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!