The chemical industry seeks novel, single active molecules which can preferably be synthesised in a laboratory. The evolutionary pressure on plants has apparently caused them to maintain an arsenal of strategically useful compounds which can be varied in response to changing ecological pressures. These needs have been met by mixtures of metabolically-related variants on particular skeletal themes, frequently complex and only isolated or synthesised with difficulty. The observed activity of crude extracts seldom can be attributed to a single molecule, but is frequently the result of several compounds acting in synergy. That commercially useful single molecules have been isolated from time to time may be attributable more to good luck than to nature's providence.
Indeed, given notable successes with 'designer' drugs produced by a rational design programme, for example histamine H2-receptor antagonists for the treatment of gastric ulcers and ^-adrenoceptor blockers for the treatment of hypertension, and given also the rapid steps being made with molecular genetic technology in the treatment of disease, one may validly ask what future is there for the more empirical approaches of screening of either naturally-occurring or synthesised compounds. In other words, will our new technologies supplant the empirical methods that have served the pharmaceutical industry so far? As Aylward (this volume) points out no approach is as clear cut as this: there is much overlap.
As more and more sophisticated high-throughput screens based on cloned enzymes or receptor markers for disease targets become available it will make sense for companies to screen whatever novel compounds are available to them, be they synthetic or natural. 'Rational' approaches, whereby a drug or pesticide is designed to fit a molecular target, require an intimate knowledge of the targets at the molecular level and the physiology of the organism in which they are contained. The cost of this basic research needs to be paid for and much has been traditionally conducted in the public sector and paid for from public funds, but more may have to be paid for by industry in the future as governments concentrate on short-term returns of their investments. Ultimately, industry will make its choices of approach on the basis of comparative cost-effectiveness. Past experience has shown that interest in natural product screening has waxed and waned in cycles and a sensible approach would be to maintain an interest in all options for some time to come.
But why should industry maintain an interest in plant chemicals when chemists can synthesise an almost limitless supply of compounds and quickly produce generics of lead molecules? Primarily because many of the active compounds produced by plants are very difficult to synthesise and are unlikely to be synthesised by chemists for a screening programme. One of the most promising new anti-cancer drugs, taxol, was discovered in the bark of the western yew, Taxus brevifolia (Kingston, 1992). Although related compounds have now been synthesised, the total synthesis of taxol is a formidable challenge and it would certainly not have been synthesised for a random screen. Moreover, taxol interacts with cellular tubulin in a way unique among drugs (Kingston, 1992) and the discovery of taxol may well stimulate new ideas for the rational approach to drug design. The example of taxol also demonstrates how the hit rate may be increased by screening taxa related to those already producing leads. Screening Taxus spp. has revealed not only new sources of taxol but also other related taxanes which may be converted synthetically to taxol or are active themselves (Kingston, 1992).
The range of novel plant chemicals available for screening can be enhanced by manipulation, for example by the induction of repressed pathways (Tallamy and Raupp, 1991) or through techniques of tissue culture. 4-Ipomeanol, which shows activity against human non-small cell lung cancer lines (Kingston, 1992), is not present in healthy specimens of the sweet potato (Ipomea batatas), but its production is induced by infection with a fungus. Plant cell cultures may also synthesise secondary products not formed in the intact plant or present in only very small amounts, indicating the presence of repressed pathways (DiCosmo and Towers, 1984; Banthorpe and Brown, 1989).
Aylward (this volume) suggests that as traditional herbal remedies are likely to be the first ethnobotanical sources screened the chances of discovery will diminish as the 25 000 or so traditional remedies are worked through, leaving the plants which are not used as remedies with a store of compounds which he considers likely to give a poorer hit rate. His assumption that plants used in traditional medicine are likely to prove the best sources of new drugs may be premature. Approximately 25% of modern prescription drugs are based on active compounds from plants; 26% of these are not based on ethnobotanical 'leads', but are the result of modern discoveries. Given that the discovery of these pre-dates modern high-throughput screening programmes, it might be anticipated that the random screening of plants may prove as rewarding as the screening of ethnobotanically-targeted species (Farnsworth, 1988; Principe, 1989). Furthermore, many of the diseases of the developed world are not the ones for which traditional remedies were used. These remedies may be active against diseases for which they were not used traditionally and they and other plants may be active in diseases not endemic to the locality in which they grow. The plant Catharanthus roseus is an example of the former case. Traditionally used for the control of diabetes it was screened initially for its hypoglycaemic activity but was later shown to be active in the treatment of cancers (Kingston, 1992). New screens are continually being developed and very few, if any, plants have been screened using all the techniques now available.
Also, the pattern of disease distribution is not static. As some diseases are brought under control others gain prominence and new ones evolve. The phenomenon of AIDS is testimony to the ability of a new disease to spread rapidly among the human population. Rational and empirical approaches are being mounted to find ways to control this disease. Screening of ethnobotanicals has already produced several compounds which inhibit the AIDS virus in vitro at many different points in the replication cycle (Fellows, 1992ft). A modification of one of these (deoxynojirimycin) is now in clinical trial (Jones and Jacob, 1991). This ability of chemists to modify natural compounds and so alter or increase their activity means that nature provides an enormous storehouse of molecules which may be modified directly or used as leads for the synthesis of analogues.
Despite the problems associated with screening plant extracts and the strictures of patent requirements and drug development laws, the case for continued exploration of ethnobotanicals is strong. The chemical arsenals of plants represent 300 million years of evolution of ecologically active compounds (Swain, 1974). The challenge of today is to convert what we intuitively perceive to be a gold mine of useful substances and information into a form which can be used in the modern world, probably as money.
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