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No decrease in rate of discovery of new natural product scaffolds between 1990 and 2015

 

Natural product libraries for drug discovery

 

Nobel prize awarded for natural product-based drug discovery

The 2015 Nobel prize in Physiology or Medicine has been awarded to three researchers for their contributions to drug discovery from natural product screening programmes [1].

Professors Satoshi Omura and William C. Campbell were awarded the prize for their discovery of Avermectin, from which the widely used anti-parasite agent Ivermectin is derived, and Professor Tu Youyou was rewarded for her contribution to the discovery of Artemisinin - the latest front-line medicine in the fight against malaria.

Avermectin’s remarkable activity was discovered by screening the conditioned media of thousands of bacteria cultured from soil samples collected by Omura’s team from around Japan. Those with promising potential were sent to Campbell’s laboratory at Merck in the US for further analysis. Campbell’s team then screened the samples for activity against parasitic worms in a mouse model. The products of one microbe in particular, (Streptomyces avermitilis, cultured from soil taken near a golf course in Ito city), demonstrated remarkable worm-killing activity, yet very low toxicity. Activity-guided separation led to the discovery of the novel compound, avermectin, with a highly unusual new scaffold. Simple modifications of this scaffold led to the development of two compounds (termed Ivermectin) which together demonstrated even lower toxicity and greater anti-parasite activity.

The impact of Ivermectin on human and animal health is difficult to overstate. The drug displays not only broad-spectrum activity against a wide array of clinically relevant parasites, but also low toxicity in animals and man. Millions of West Africans have been spared the blight of river blindness (caused by the parasitic worm Onchocerca volvulus), or lymphatic filariasis (also caused by parasitic worms), largely due to the impact of Ivermectin. The drug is now included on the World Health Organization's List of Essential Medicines - those which are considered to be the safest and most effective in modern healthcare.

A more focussed natural product screening approach was taken to the discovery of Artemisinin. Following an outbreak of malaria strains resistant to the anti-malarial drug chloroquine, the Chinese government initiated a state-wide effort to identify new anti-malarials. In the early years of the initiative, ~40,000 synthetic compounds were screened, but without success. Mindful of this, Youyou’s team aimed to maximise the chances of success by focussing their screens on phytochemicals, together with evidence from a collation and reappraisal of ancient texts relating to Chinese traditional medicines. Those plants reportedly prescribed for fever or other symptoms of malaria were of particular interest, and were selected for biological assay. These ethnopharmacologically focussed screens led to the discovery that cold water extracts of Artemisia annua L. (sweet wormwood), displayed remarkable activity against malaria parasites. Activity guided separation enabled the identification of a highly complex molecule with activity against several Plasmodium species, but low toxicity in mice. The unusual endoperoxide ring of the compound was found to be essential for antiparasite activity, but unlike anything a chemist could synthesise, or likely had conceived of before. Artemisinin-based therapies are now the recommended first-line therapy for P. falciparum malaria globally, and are estimated to have saved millions of lives to date [2].

These two wonderful examples of the successful application of natural product screening programmes lend further proof to the immense potential of natural compounds, particularly when coupled with the rich evidence base from traditional medicine, for the development of new drugs. As our medical needs transition away from infectious disease towards chronic non-communicable diseases over the coming decades, returning to these rich resources is likely to be critical in our efforts to develop the next generation of therapeutic compounds.

[1] Shen B. A New Golden Age of Natural Products Drug Discovery. Cell 163:1297-1300 (2015)
http://www.cell.com/cell/fulltext/S0092-8674(15)01550-0

[2] Su X, Miller LH. Artemisinin: discovery from the Chinese herbal garden. Cell 146:855-858 (2011)
http://www.cell.com/cell/fulltext/S0092-8674(11)00950-0

Natural product libraries for drug discovery

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