a national research and development platform for novel drug development from indigenous medicinal plants

Introduction
The project aims to develop (1) new medicines, effective against tuberculosis, malaria, diabetes mellitus and for immune modulation and (2) tonics from indigenous southern African plants and local knowledge. Successful conclusion of the project is expected to make possible the discovery of novel drugs and tonics, to the point of proof of principle, over the three-year time span of the project, suitable and ready for early clinical studies, patenting, and further development in conjunction with an industrial partner, the World Health Organization, or other collaborative arrangements that should be profitable and contributory to public health and specifically to the management of the serious and comparatively neglected diseases against which this research activity is intended.

Problem statement
There is a continuing trend indicating that the global pharmaceutical industry is suffering from declining productivity (fewer new medicines are introduced despite increased spending on research)⁽¹⁾ . Yet there is increasing need for innovation in selecting therapeutic targets and finding lead compounds. The vast majority of current drug discovery carried out by the pharmaceutical industry relies on molecular approaches, involving defined molecular targets. And molecular approaches in turn are dominated by high throughput screening. The pharmaceutical companies that have the best and most diverse chemical collections will ultimately dominate the industry ⁽²⁾. Broadly speaking, such chemically diverse collections can only come from two main sources of large numbers of compounds: combinatorial chemistry and natural products. Although combinatorial chemistry can provide large numbers of compounds for high throughput screening they tend to have limited structural diversity. In contrast, natural products provide a wealth of small molecules with drug-like properties and with incredible structural diversity ⁽³⁾.

The most common therapeutic areas for natural product-based drugs are cancer, followed by metabolic diseases (mainly diabetes mellitus and obesity), then anti-infective agents (antibacterial, anti-fungal and antiviral) and neuropharmacological agents (including analgesics)⁽⁴⁾. There is a vast resource of biodiversity that has not yet been tested for useful pharmacological activity. Even with higher plants, which probably represent the most thoroughly examined source, it is estimated that less than 10% of the world's species have been tested for biological activity⁽⁵⁾ . It has been pointed out that of the 20 best selling non-protein drugs in 1999, nine were either derived from, or developed as a result of, leads generated by natural products ⁽⁶⁾.

Brief methodology

• Specialists from a number of clinical and scientific disciplines will collaborate to develop and apply selection criteria aimed at identifying plants with the highest potential for the selected diseases
• A dedicated and comprehensive electronic database will be taken to advanced stage (it already exists) to facilitate this approach, covering African (principally southern African) plants.
• Candidate plants will be processed and extracted under GLP conditions and screened for in vitro activity.
• Promising candidates identified after bio-assay will be selected for further work, and extracted in sufficient quantities and high purity for further investigation and development.
• Once the chemical structure(s) of the active compounds have been determined, candidate molecules will be analysed retrosynthetically in order to identify readily available and/or accessible starting materials
• A clinical trial platform will be established in order to bring the evidence to the point of proof of concept.
• Subsequent pharmaceutical and manufacturing development, after establishing proof of principle, will be conducted in collaboration with pharmaceutical chemists and with the pharmaceutical industry (industrial collaboration will be with South African partners, and in particular with the generic pharmaceutical industry will happen).

Novelty
The special feature of this project is that it will be done on southern African indigenous plants by South African researchers, and it contains all the necessary elements required in drug discovery to take the process through from plant to drug. This consortium brings together the potential to integrate the strengths of microbiology, chemistry, pharmacology and botany so as to make a considerable and unique contribution to the search for novel drugs in southern Africa and more widely on the African continent. Many of the plants that will be investigated are endemic to southern Africa, providing opportunities for discovery that are not available elsewhere. The 24 000 southern African terrestrial plants, of which 4 000 have medicinal significance, and the diverse marine plant flora of which little medicinal application is known, have the potential to expand enormously the search for novel anti-disease compounds.

Outcomes

• Development of effective and safe novel drugs for malaria, TB, diabetes and immuno-modulators (altogether, 2-3 are anticipated)
• Substantial revenues from transfer of technology
• Creation of agro-processing opportunities in SA
• Patents on novel plant-derived compounds
• Placing SA as an international factor in development of plant-derived medicines
• Establishment of a competent and experienced multidisciplinary team for drug development work in the country
• Development of a national research and development platform for cost-effective and standard screening of new drug entities of medicinal plant origin
• Making generally and readily available to the South African research community highly effective, standard and validated fractionation methods
• Making available to the research community a database and herbarium related to medicinal plants
• Establishment of a feedback channel for benefits to the source communities

Consortium members

1. Scrip Reports, 2001: Natural Product Pharmaceuticals: A diverse approach to drug discovery
2. Stroh, 2000: Drug Discovery Today
3. Scrip, Reports, ibid
4. Pharmaproject, 2001
5. Verpoorte R, 1998: Drug Discovery Today, 3, 232-238
6. Scrip, ibid

Contact details:
Prof Peter Folb (Project Leader)
Dr Niresh Bhagwandin (Project Manager)
Medical Research Council of South Africa
P O Box 19070, Tygerberg, 7505 Cape Town
Tel: 021 938 0207 / Fax: 021 938 0460
E-mail: niresh.bhagwandin@mrc.ac.za