One of the best places to seek novel compounds for pharmaceutical drugs, alternative energy sources, and a host of industrial applications, is within natural systems that have evolved over millions of years. Scientists now realise that the precise molecular arrangements within natural pathways in organisms have been highly tuned for specific processes and provide both compounds that can be exploited directly and vital information over how to synthesise new products by mimicking biochemical processes. Dr.K.C. Nicolaou spoke with Scientist Live recently about searching for potential drugs within nature.
Can you explain why the "natural products pathway" holds so much potential in terms of drug discovery?
The "natural products pathway" to drug discovery, as you call it, has a proven record of success that speaks volumes for its future. Success stories like those of Aspirin®, penicillin, and Taxol® are but a few of its glorious past. In fact it has been estimated that over 60% of the drugs on the market today have their origin in some way or another from nature. If you consider this together with the fact that the molecules we have isolated from nature thus far represent only the tip of the iceberg of what is out there, then you can appreciate why this natural pathway holds so much potential in terms of drug discovery. The main reason why natural products are such good leads for drug discovery is that most of them come with important biological properties. They have been evolved to bind to biological receptors as part of the living world and, therefore, are likely to exert interesting biological activities that often have relevance to disease.
What are some particularly promising avenues of research and how are they being pursued?
Natural products have been particularly successful medicines against infectious disease and cancer. So there is a lot of research being carried out in pursuit of new anti-infectives and chemotherapeutic agents. Typically scientists look for such compounds in the forest (plants and trees), the soil (bacteria and fungi), and the ocean (marine creatures). Samples of various species - some more exotic than others - are collected from around the globe and brought back to the laboratory where they are carefully studied to reveal their molecular secrets. The new molecules so discovered are then tested by biologists for their possible therapeutic actions against disease. Current efforts are focused on new anticancer agents, new antibiotics particularly active against drug resistant bacteria, possible treatments of HIV/AIDS, and Alzheimer's disease.
In the press release associated with the ESF-COST conference, you made the differentiation between herbal medicine and your research. Can you elaborate on the differences? What is the difference between the products that result from the more chemical/scientific approach and herbal remedies that may contain similar chemicals?
Herbal medicine has been practiced for thousands of years beginning in the Middle East and the Orient. Such recipes often contain mixtures of compounds extracted from natural sources. They were developed without proper clinical trials, so their efficacy and safety have not been rigorously and systematically determined. In contrast, modern drug discovery and development follows strict scientific methods of investigation, usually of single compounds whose efficacy and safety profiles are systematically determined through toxicological and clinical trials. This process obviously ensures quality control and results in widely accepted medicines of proven value to the patient. So while herbal medicines may provide beneficial effects, they are not as well defined as modern medicine is. Natural products like the ones we are studying are part of the modern medicine cabinet. The latter are pure, single compounds and not cocktails of compounds as those found in herbal or folk medicines. One, however, should not underestimate the value of folk medicines, for they provide interesting clues that may lead scientists to the magic ingredient which can then be developed as a pure substance into a modern and highly effective drug.
What is your particular area of expertise? Can you give a overview of what you are exploring and its possibilities?
My research group, like many others around the world, is involved in the chemical synthesis of complex and biologically active natural products, molecules discovered by other scientists in the forest, the soil, or the ocean. There are several reasons why one wishes to synthesise such molecules. One good reason is the fact that these molecules are often scarce and cannot be harvested from their natural sources in large enough quantities to allow their thorough biological investigation, so chemical synthesis becomes the only available means to produce them. In cases where these molecules are complex in terms of their molecular structures, the laboratory synthesis is far from trivial. The synthetic chemist has to develop ingenious and multi-step synthetic strategies to reach them, through campaigns that may, sometimes, take years to develop. But once developed, such processes can provide large quantities of these precious molecules for further biological studies in order to determine their potential as medicines. Most importantly, these technologies allow the synthetic chemists to go beyond nature and synthesise designed versions of the natural molecules that can then be tested in search of superior pharmacological properties. Such improved molecules may then lead to drugs with higher potencies and less side-effects from the ones nature provides. Following this approach, which obviously takes its lessons from nature, we are currently following leads for new antibiotics and anticancer drugs.
As an example of our anticancer research, I can mention the epothilones, a class of naturally occurring molecules originally discovered from a species of bacteria that were found in dirt collected from the banks of the Zambezi River in southern Africa. Following our successful campaign to construct them in the laboratory, we proceeded to design and synthesize numerous analogs of the natural molecules, eventually discovering more powerful anti-cancer agents. Some of these compounds are now in further development. A similar story is currently developing in our laboratory in the area of antibacterial agents effective against drug resistant bacteria. In this case too, the lead compound came from nature. Coined platensimycin, this natural product was first reported by Merck scientists in 2006 and demonstrated powerful activities against all drug-resistant bacteria tested, an impressive and exciting prospect considering the increasing menace posed by such bacterial strains to humanity. Our group was the first, among over a dozen groups by now, to synthesize platensimycin. The search is now on for a superior molecular version of this natural antibiotic that will, hopefully, surpass it in terms of potency and pharmacological properties as a potential drug against these frightening pathogens. Next, who knows, we may get involved in the area of Alzheimer's disease which is a major challenge for science and medicine, made even more acute as the ageing population increases around the world. Indeed, nature may hold some secrets in this regard too, for example within the extracts of "Ginkgo Biloba," a herbal medicine that some believe has beneficial effects on memory and cognitive function.
Are there any limitations to the "natural pathway" approach to discovering new compounds?
Of course, despite the success and future promise of the "natural pathway" to drug discovery, modern medicine has demonstrated an alternative and complementary approach to drug discovery. This approach, which also relies on chemical synthesis, involves man-made molecules. These molecules are not found in nature, but are rather designed and synthesised by chemists in the laboratory. In this approach, high-throughput biological screening of large numbers of such compounds (often referred to as compound libraries), a few lead compounds are discovered, which are then fine-tuned by chemists in order to optimise their pharmacological properties, leading to drug candidates for further development. The two approaches are complementary to each other and are both considered by many as productive and worthwhile avenues to drug discovery. Although more tedious and expensive, the "natural pathway" may provide larger dividends in terms of gaining new and fundamental knowledge in chemistry and biology, and may result in new paradigm and block-buster drugs as demonstrated recently with FK506 and rapamycin (immunosuppressive drugs used in transplantations), Taxol® (anticancer drug), and the statins (cholesterol lowering drugs).
At this point, what is the next step for this area of research?
Given the relatively high cost and the fact that natural products based drug discovery requires considerable patience, and because of the seemingly attractive nature of other approaches to drug discovery such as combinatorial chemistry and biologics, pharmaceutical companies and funding agencies have, in recent years, decreased their investments in the former area of research. Thankfully, there are signs that this trend is now changing, perhaps partly because of the apparent scarcity of new drug approvals in recent years and the disappointing current drug development pipelines. What is needed, in my opinion, in this area of research is to invest in it more time and effort so as to allow exploration of the incredible biodiversity that exists on our planet. Our forests and our oceans are still, to a large extent, unexplored despite the secrets they are certain to hold. Such explorations will yield, in turn, an amazing molecular diversity that will reveal new biology and inspire new chemistry and new pathways to much needed cures. Millions of species are in danger of extinction and they will take with them their molecular secrets. It will be a shame to loose them both, for besides the damage that such catastrophe will bring to nature, this extinction may also shut the "natural pathway" to discovery, denying humanity, perhaps forever, the knowledge required for the next generation of cures.
(More about stories of drugs discovered from nature can be found in a recent book by K.C. Nicolaou and Tamsyn Montagnon titled Molecules that Changed the World (2008, Wiley-VCH).)
(Reporting by Marc Landas)
