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Natural products are the most consistently successful with combined annual sales of .US$16 billion. Newer
developments based on natural products include the anti-
source of drug leads. Despite this, their use in drug
malarial drug artemisinin and the anticancer agents taxol,
discovery has fallen out of favour. Natural products docetaxel and camptothecin (Fig. 2) (for more examples,
continue to provide greater structural diversity than see Refs 3–5). Therefore, the use of natural products has
been the single most successful strategy for the discovery
standard combinatorial chemistry and so they offer
of new medicines.
major opportunities for finding novel low molecular In addition to this historical success in drug discovery,
weight lead structures that are active against a wide natural products are likely to continue to be sources of
new commercially viable drug leads. The chemical novelty
range of assay targets. As less than 10% of the associated with natural products is higher than that of any
world’s biodiversity has been tested for biological other source: 40% of the chemical scaffolds in a published
database of natural products (Dictionary of Natural
activity, many more useful natural lead compounds
Products, Chapman & Hall) are absent from synthetic
are awaiting discovery. The challenge is how to chemistry6. This is particularly important when searching
access this natural chemical diversity. for lead molecules against newly discovered targets for
which there are no known small-molecule leads. Despite
the commonly held assumptions, natural products can be
a more economical source of chemical diversity than the
pproximately 60% of the world’s population synthesis of equivalent numbers of diverse chemicals.
Alan Harvey, Drug Discovery Ltd, Royal College Building, 204 George Street, Glasgow, UK G1 1XW. tel: +44 141 548 4534,
fax: +44 141 552 8376, e-mail: a.harvey@drugdiscovery.co.uk
294 1359-6446/00/$ – see front matter ©2000 Elsevier Science Ltd. All rights reserved. PII: S1359-6446(00)01511-7 DDT Vol. 5, No. 7 July 2000
research focus REVIEWS
Table 1. Strategies to expand the range of natural products available for drug discovery screening
Untapped geographical Drug Discovery Plant-based diversity has been Concerns over sustainability of
sources historically successful natural collecting
Preparation of libraries Analyticon More compatible than mixtures for HTS Cost of production
of isolated compounds Molecular Nature
Marine sources PharmaMar Unusual chemistry Identification of source organisms
Australian Institute Recollection difficult on large scale
for Marine Sciences
Insects INBio Little studied Scale-up potentially difficult
CSIRO (Entomology)
Plant tissue culture Phytera Control over genetic pathways Concerns over access to genetic
material sourced from
developing countries
Combinatorial genetics Kosan Biosciences Convenient production using Restricted range of structures
Galilaeus Oy fermentor technology
Terragen
can be found by comparisons with absorbance spectral living cells in each millilitre30. However, most drug discov-
libraries of known molecules21. ery from marine sources involves much larger organisms –
Since the introduction of the CBD, there has been little plants or animals. The sea covers 70% of the earth’s sur-
progress in accessing plant material from more diverse face and is home to examples of most types of organism:
geographical areas. The collection programme of the there could be .10 million species of marine macro-
National Cancer Institute (Frederick, MD, USA) continues22 fauna35. Again, very few species have been used for drug
and there are some regional initiatives, such as the Biore- discovery purposes, and the ones that have been used are
sources Development and Conservation Programme (Silver from a restricted range of phyla, with sponges (Porifera)
Spring, MD, USA) in parts of Africa23 and the Indian Coun- and seamats (Bryozoa) being most popular16,36,37. Despite
cil for Scientific and Industrial Research’s Coordinated this, unusual chemical structures have been isolated and
Programme on Bioactive Molecules from Natural Product several compounds of marine origin (mainly potential anti-
Sources (New Delhi, India). These tend to focus on the cancer agents37) are in clinical trials, including aplidine
exploration of plants that have a history of use in systems and ecteinascidin 743. There are specialist companies
of traditional medicine. For a broader range of plant biodi- (e.g. PharmaMar, Madrid, Spain) and institutes (e.g. the
versity, Drug Discovery (Glasgow, UK) has established a Australian Institute for Marine Sciences, Townsville,
network of collaborators in 20 different countries to build Queensland, Australia) that are amassing large collections
up a very diverse range of species. Its collection of of marine samples for drug discovery.
approximately 5000 species come from 70% of the known
plant families in the world. New organisms
As well as looking in relatively unexplored habitats, drug
Microbial diversity discovery efforts can be applied to groups of novel organ-
Microorganisms have been exceptionally rich sources of isms. For example, there are thought to be 30 million
drugs, including antibiotics, immunosuppressants and the species of insect17 but very few of them have ever been
lipid-lowering statins. However, these drugs have been available for screening for therapeutically relevant mol-
produced from a very small range of the world’s microbial ecules. The collaboration between Merck (Rahway, NJ,
diversity24,25, and how many species of microorganism USA) and the Instituto Nacional de Biodiversidad
there might be is not known. Only approximately 6000 (Heredia, Costa Rica) has stimulated the collection of insect
bacterial species have been named (compared with more samples from Costa Rica38, but the outcome of any screen-
than a million plants and animals) and estimates of ing is not yet known. In Australia, the Entomology branch
1.5 million species of fungi and 1.5 million species of of the Commonwealth Science and Industrial Research
algae and prokaryote17 might have to be revised upwards. Organization (Canberra, ACT, Australia) provides extracts
With the availability of techniques to sequence ribo- of insects for screening purposes. However, the difficulties
somal RNA genes extracted and cloned from natural envi- of collection, identification and scale-up are formidable.
ronments, it appears that less than 1% of microbial diver- Without positive examples of unique chemical diversity
sity has been cultured and studied experimentally26,27. from insects, it is hard to see a major growth in screening
Bacteria are also being found in surprisingly extreme envi- of samples from this particular source of biodiversity.
ronments: polar ice28–30, geothermal vents31,32, dark caves33
and deep-sea sites34. One species (Pyrolobus fumarii) Cone snails
grows at 90–1138C and makes metabolic energy by oxidiz- Another rather inaccessible source of novel chemicals is
ing diatomic hydrogen with nitrate, producing ammonia31. the Conus genus of marine snails. However, cone snail
With so many organisms with metabolic pathways adapted venoms are a particularly rich source of pharmacologically
to such a range of environments, an unusual array of active peptides, acting on a variety of receptors and ion
chemicals might be produced that could add to the diver- channels39. One particular conopeptide, v-conotoxin
sity of any screening library. As described below, tech- MVIIA from Conus magus, is in Phase III clinical trials for
niques are being developed to make use of genes isolated the treatment of intractable pain; it acts as a specific
from unusual organisms in more manageable systems24. blocker of N-type calcium channels in the pain fibres of
the spinal cord40. With this successful example of a use for
Beneath the sea a conopeptide, Conus venoms can be expected to be
One of the findings of the new techniques for detecting actively searched for novel lead structures41. Moreover, of
bacteria was that sea water contains up to a million free- the 500 known species of Conus, only about a dozen have
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Collaboration…
American Home Products Corporation (AHP; Madison, NJ, USA) have formed a collaboration with Elan Corporation (Dublin,
Ireland) to develop a vaccine for the treatment of mild to moderate Alzheimer’s disease and possibly also for the prevention of disease
onset. The two companies will collaborate in research, development and commercialization of AN1792. In preclinical studies, Elan has
shown that this product reduces and prevents the development of amyloid plaques in transgenic mice, and they have commenced
Phase I human safety studies in Alzheimer’s patients in the US and the UK. The collaboration will include a five-year research program
for the discovery and characterization of additional products. AHP will make an initial payment to Elan and additional payments will be
made for key development benchmarks and regulatory milestones. Costs and revenues from AN1792 and other products developed
will be shared equally by the two companies.