Exploring the Potential of Natural Products in Pharmaceutical Industry

1. Lecture 7 – NPs and The Pharmaceutical Industry

2. Artemisinin treats multi-drug resistant strains of malaria. It is a sesquiterpene lactone fom the shrub Artemisia annual. Apparently it is only produced when the plant is subjected to certain conditions. Wikepedia Artemisinin

3. Lecture 7 – NPs and The Pharmaceutical Industry • Learning Outcomes - at the end of the lecture you should: • Appeciate the importance of NPs as pharmaceutical agents • Understand what we mean by Bioprospecting • Appreciate why some environmentalists got excited by this possible means of funding conservation • Appeciate • 4.1 Why the potential of bioprospecting may have been greatly overplayed • 4.2 Why the screening hypothesis questions the underlying scientific rationale • 4.3 Why the behaviour of pharmaceutical companies supports this analysis • 4.4 How “bioprospecting” might be done in future

5. Finding new drugs - which is the way ahead? Preserving biodiversity Finding new NPs Exploiting ethnobotanical knowledgeExploiting ecological knowledge Combinatorial chemistry Rational drug design High throughput screening OR Throughout the 1990s this was the approach adopted by most companies – but has it failed? Many environmentalists and some environmental economists say that the future lies with NPs - BIOPROSPECTING

6. Finding new drugs – BIOPROSPECTING? Google finds 58000 references to Bioprospecting ( 2005) and 489,000 now!

8. Bioprospecting – money for conservation? • World sales of pharmaceuticals are currently about $400 billion annually (25% in these sales are in LDC and 75% in the others) • 25-50% of pharmaceutical drugs contain natural products or compounds derived from natural products • Balick & Mendelsohn (1992), studying the harvesting of medicinal plants from a rain forest estimated that annual revenues of $16-61 per ha could be achieved. • Pearce & Puroshothamon (1995) estimated that OECD countries might suffer an annual loss of £25 billion if 60,000 threatened species were actually lost as a medicinal resource. • Merck & Co. entered into a bioprospecting agreement ($1 million) with the National Institute for Biodiversity (INBio) in Costa Rica in 1991 and Eli Lilly made an investment in Shaman Pharmaceuticals

9. Bioprospecting – money for conservation? • G C Rausser & A A Small (2000) J Political Economy, 108, 173-206 • “Numerical simulation results suggest that, under plausible conditions, the bioprospecting value of certain genetic resources could be large enough to support market-based conservation of biodiversity”

10. G C Rausser & A A Small (2000) J Political Economy, 108, 173-206 • However, their analysis is too simplistic. • Total cost of drug (T) = Drug Discovery (A) • + clincal studies (B) + safety testing (C) + drug manufacture (D)+ IPR (E) + etc. • A1. obtaining chemical samples • A2. testing the samples for a useful biological effect • B. efficacy of the drug in clinical trials (e.g. does the effect found in the test tube translate into a positive outcome for the patient?) • C. safety testing (e.g. are there adverse side effects due to the chemical having more than one effect?). Will include metabolism studies and long term animal studies. • D. manufacturing methodologies (e.g. can the chemical be extracted, synthesised or produced by fermentation on an industrial scale economically?) • E. intellectual property (e.g. can the drug and its derivatives be adequately protected by patents?)

11. G C Rausser & A A Small (2000) J Political Economy, 108, 173-206 • They ignore that fact that making a Natural Product in commercial quantities is often very hard indeed and often too expensive to lead to a viable product unless it is a very important treatment. Progesterone Vinblastine Streptomycin Taxol

12. Liquorice or licorice is the root of Glycyrrhiza glabra, from which a sweet flavour can be extracted. Liquorice extract is produced by boiling liquorice root and subsequently evaporating most of the water. Its active principle is Glycyrrhizin, more than 50 times as sweet as sugar.

13. Bioprospecting – leads to conservation? • TAXOL – a highly successful anti cancer drug • Extracted from the bark of the Pacific Yew Taxus brevifolia • 3000 trees to get 1 kg – the trees die when the bark is taken • 75,000 trees pa needed to treat ovarian cancer in the USA • No economic synthesis available

14. Bioprospecting – evidence of enthusiasm? • Merck’s $1million invested in INBio – impressed? • Merck’s 2003 sales were $20,130 • Merck’s R&D 2003 R&D budget $3,957 million • Was the investment in INBio from the R&D budget or their PR budget?

15. So where will future generations of drugs come from? Preserving biodiversity Finding new NPs Exploiting ethnobotanical knowledgeExploiting ecological knowledge Combinatorial chemistry Rational drug design High throughput screening OR Maybe neither • NPs can have specific, potent biomolecular activity • They are very often very difficult to make synthetically • The majority of organisms making NPs may not even be accessible - < 10% of microbes can be cultured

16. So where will future generations of drugs come from? • Genetically manipulated microbes? • Choose a microbe that makes a good range of chemical diversity and can be cultured on a large scale • Add a gene coding a NP producing enzyme from another organism • Look for new chemical diversity • Repeat and repeat and repeat with different genes … from plants, from unculturable microbes, etc.. Combinatorial biochemistry.

17. Summary • NPs are very important in the huge pharmaceutical industry • NPs could become more important again • Bioprospecting has been oversold by environmentalists. We should not rely on income streams from bioprospecting for conservation. • The Screening Hypothesis could be a more productive guide to the pharmaceutical industry than previous models