From natural products to drugs

Since the last century natural products have played a major role in the chemotherapy of parasitic diseases, with quinine, emetine and berberine being used to treat malaria, amoebiasis and leishmaniasis, and santonin used for the treatment of helminth infections. The discovery of artemisinin, the antimalarial component of Artemisia annua, by Chinese scientists in the early 1970s has refocused attention on the potential of plant products in the treatment of parasitic diseases, especially malaria [1]. By the early 1980s the impact of artemisinin on malaria treatment in south-east Asia was comprehensively reported [2]. A range of semi-synthetic derivatives of this remarkable compound have already come to market, including arteether (artemotil), β-artemether, artesunate, the combination of artemether and lumefrantine (Co-Artem; Novartis, Basel, Switzerland), suppository formulations of artesunate or dihydroartemisinin, and the established artesunate plus mefloquine combination now available in blister packs [3]. Interest in artemisinin and its derivatives continues. The article by Haynes (pp. 719-726) shows how limited our knowledge of the pharmacology and toxicology of these compounds is (in particular how they are metabolized), while other reviews published this year have illustrated the gaps in our understanding of their mechanisms of action [4,5]. Importantly for future antimalarial development, there has been progress in the synthesis of synthetic tetroxane, trioxane and dioxane derivatives of artemisinin (Haynes, pp. 719-726) [6-8]. The research and development of one group of such structures is currently supported by the public-private partnership Medicines for Malaria Venture (MMV). The major goals of this research are to not only improve activity, but also improve pharmacological performance. There is also interest in the synthesis of hybrid artemisinin molecules [9]. Another plant product with antimalarial activity, licochalcone A, isolated from the Chinese liquorice root Glycyrrhiza spp. [10], has also become the focus of commercial venture. Since the initial report of its anti-Plasmodium activity, there have been efforts to identify synthetic lead derivatives [11]. A Danish company (LICA Pharmaceuticals, Copenhagen, Denmark; see website http://www.licapharma.com) has been founded with the specific mission to develop licochalcone derivatives for malaria and other infectious diseases. Other companies producing plant products also have the antimalarial market in sight. Voacamine is an alkaloid derived from Peschiera fuchsiaefolia from South America. Despite limited anti-Plasmodium activity in experimental models [12], voacamine is a component of a formulation known as MalarexTM (Millenia Hope Inc, Montreal, Canada; see website http://www.malarex.com) which is being considered for export from America to Africa as an antimalarial. Plants are not the only natural source of novel antimalarial products: the marine sponge-derived alkaloid manzanine has demonstrated significant experimental antimalarial activity [13]. Nevertheless, whatever the source and traditional origins, before clinical use any natural product needs to be subjected to the same regulatory authorities as synthetic antimalarials. Antibiotics, also natural products derived from fungi or bacteria, have remained the core of antibacterial chemotherapy but have not featured large in the antiparasitic repertoire, and their use for this purpose is rarely discussed [14]. Although there is continued interest in use of the polyene amphotericin B and the aminoglycoside paromomycin for leishmaniasis, and tetracyclines for malaria, there have been few novel leads and little chemistry to optimize antiparasitic activities. It is therefore of interest that the antibiotic peptide apicidin, an inhibitor of histone deacetylase, has been extensively derivatized to give a number of potential antiprotozoal compounds, indicating the wider promise of such an approach [15-17]. There are two other foci of interest on antibiotics as antiparasitics. Firstly, the observations of the effects of this class of drugs on filarial worms are described by Taylor and Hoerauf (pp. 727-731) and show how antiparasitic activities are not necessarily always direct, in this case through the killing of endosymbiont bacteria. Secondly, the unique plasmid, the apicoplast, in apicomplexan parasites is derived from endosymbiont cyanobacteria [18]. This renders Toxoplasma gondii and Plasmodium sensitive to a range of antibiotics, an approach recently explored through both structure-activity and mechanistic studies [19,20]. These antibiotic-sensitive metabolic pathways might lie within the plasmid itself or be expressed in the cytoplasm, for example, isoprenoid biosynthesis sensitive to fosmidomycin [21,22] or fatty acid biosynthesis sensitive to the antibacterial agent triclosan [23,24]. There have been significant changes in the antiprotozoal landscape in the past year. The shape of the MMV public-private partnership, which aims to build a pipeline sufficient to produce one new antimalarial drug every 5 years, has now emerged (see website http://www.mmv.org). Such partnerships offer a suitable structure to encourage large pharmaceutical companies like Glaxo SmithKline (Greenford, Middlesex, UK) fully to participate in the discovery and development process. Other pharmaceutical companies, such as Aventis (Strasbourg, France), Bristol-Myers Squibb (New York, New York, USA) and Bayer (Leverkusen, Germany) have undertaken to ensure supplies of eflornithine, melarsoprol, pentamidine and nifurtimox for the treatment of human African trypanosomiasis for the next 5-year period, with distribution managed by the World Health Organization and Médecins Sans Frontières. The next step forward must be to ensure a system for the development of new drugs for the trypanosomiases and leishmaniases. This support, together with the strategic approach of therapeutic switching, could soon bring new drugs to clinical trial for these trypanosomatid diseases. Contacts with pharmaceutical companies have enabled Urbina (pp. 733-741) and colleagues to identify several antifungal sterol biosynthesis inhibitors with activity against both acute and chronic Trypanosoma cruzi infections in experimental models, which could move to clinical trials for Chagas disease; support for this approach to engage industry must be encouraged.

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