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Drugs Against Parasitic Diseases: R&D Methodologies and Issues Discoveries and Drug Development DrugsDrugs againstagainst parasiticparasitic diseases:diseases: R&DR&D methodologiesmethodologies andand issuesissues DiscoveriesDiscoveries andand drugdrug developmentdevelopment Edited by A.H. Fairlamb, R.G. Ridley, H.J. Vial TDR/PRD/03.1 Copyright © World Health Organization on behalf of the Special Programme for Research and Training in Tropical Diseases 2003 All rights reserved. The use of content from this health information product for all non-commercial education, training and information purposes is encouraged, including translation, quotation and reproduction, in any medium, but the content must not be changed and full acknowledgement of the source must be clearly stated. A copy of any resulting product with such content should be sent to TDR, World Health Organization, Avenue Appia, 1211 Geneva 27, Switzerland. TDR is a World Health Organization (WHO) execut- ed UNDP/World Bank/World Health Organization Special Programme for Research and Training in Tropical Diseases. This information product is not for sale. The use of any information or content whatsoever from it for publicity or advertising, or for any commercial or income-generating purpose, is strictly prohibited. No elements of this information product, in part or in whole, may be used to promote any specific individual, entity or product, in any manner whatsoever. The designations employed and the presentation of material in this health information product, including maps and other illus- trative materials, do not imply the expression of any opinion whatsoever on the part of WHO, including TDR, the authors or any parties cooperating in the production, concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delineation of frontiers and borders. Mention or depiction of any specific product or commercial enterprise does not imply endorsement or recommendation by WHO, including TDR, the authors or any parties cooperating in the production, in preference to others of a similar nature not men- tioned or depicted. The views expressed in this health information product are those of the authors and do not necessarily reflect those of WHO, including TDR. WHO, including TDR, and the authors of this health information product make no warranties or representations regarding the con- tent, presentation, appearance, completeness or accuracy in any medium and shall not be held liable for any damages whatso- ever as a result of its use or application. WHO, including TDR, reserves the right to make updates and changes without notice and accepts no liability for any errors or omissions in this regard. Any alteration to the original content brought about by dis- play or access through different media is not the responsibility of WHO, including TDR, or the authors. WHO, including TDR, and the authors accept no responsibility whatsoever for any inaccurate advice or information that is pro- vided by sources reached via linkages or references to this health information product. Layout: Lisa Schwarb Drugs against parasitic diseases: R&D methodologies and issues Discoveries and drug development UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) CONTENTS Introduction . 5 Scope of the book . 8 SECTION I: Global picture of antiparasitic drugs and need for control strategies. Economic and patent issues Robert Ridley (Geneva, Switzerland): The need for new approaches to tropical disease drug discovery and development for improved control strategies . 13 Patrice Trouiller (Grenoble, France): Drug development and registration for parasitic diseases: what are the barriers . 23 Mamadou Traoré (Brussels, Belgium): Role of endemic countries in research and development . 31 Palle Jakobsen (Bagsvaerd, Denmark): Patent policy and strategies for tropical diseases . 35 SECTION II: How to discover novel targets for pharmacological intervention Alister Craig (Liverpool, UK) with Paul Horrocks, Sharen Bowman, Susan Kyes, Andrew Waters: Entering the post-genomic era of malaria research . 41 Sara Melville (Cambridge, UK): Characterisation and sequencing of the Trypanosoma brucei genome . 63 David Parry-Smith (Cambridge, UK): Overview of bioinformatics and applications in drug discovery . 75 Pierre Casellas (Montpellier, France) with Pascale Cohen, Monsif Bouaboula, Omar Jbilo, Michel Bellis: DNA chips: applications in pharmacology . 83 Christopher Gray (Basel, Switzerland): Bacterial targets and antibiotics: genome-based drug discovery . 91 2 Drugs against parasitic diseases: R&D methodologies and issues • CONTENTS SECTION III: Compound acquisition and rational for drug development Jean Martinez (Montpellier, France) with Gilles Subra: Combinatorial chemistry: a new tool for the search of biologically active molecules . .101 Alan Fairlamb (Dundee, UK): Target discovery and validation with special reference to trypanothione . 107 Hagai Ginsburg (Jerusalem, Israel): Targets for antimalarial drug development derived from basic research . 119 Michael Gelb (Seattle, USA): Protein prenylation in Trypanosomatids: a new “piggy-back” medicinal chemistry target for the development of agents against tropical diseases . .129 Paul Michels (Louvain, Belgium) with Barbara Bakker, Fred Opperdoes, Hans Westerhoff: On the mathematical modelling of metabolic pathways and its use in the identification of the most suitable drug target . .135 Gerhard Bringmann (Wuerzburg, Germany): From tropical lianas to novel antiplasmodial agents: the naphthylisoquinoline alkaloids . .145 SECTION IV: Methods for drug screening and evaluation of pharmacological activity David Fidock (New York, USA) with Amar bir Singh Sidhu, Thomas Wellems: The molecular basis of Plasmodium falciparum chloroquine resistance . 153 Simon Croft (London, UK) with Reto Brun: In vitro and in vivo models for the identification and evaluation of drugs active against Trypanosoma and Leishmania . .165 Clemens Kocken (Rijswijk, The Netherlands) with Martin Dubbeld, Annemarie van der Wel, Alan Thomas: Animal models in antimalarial drug development . .177 Pascal Ringwald (Geneva, Switzerland) with Leonardo Basco: In vitro and in vivo chemosensitivity tests for malaria . .185 Piero Olliaro (Geneva, Switzerland) with Walter Taylor: Multidrug therapy to delay antimalarial drug resistance . .193 Julio Martin (Madrid, Spain): Screening methodologies for chemotherapeutic targets. High-throughput screening as an essential complement to the genomic approach. Advanced technology to assist high-throughput screening . 199 LIST OF PARTICIPANTS . 209 Drugs against parasitic diseases: R&D methodologies and issues • CONTENTS 3 INTRODUCTION Discovery and drug development for tropical diseases: new opportunities, new trends iewed globally, parasitic diseases pose an increasing threat to human health and welfare. Leishmaniasis and trypanosomiasis continue as a V cause of suffering for many millions of people in both tropical and subtropical zones of the world and in the last 25 years, malaria has made a comeback and remains one of the greatest threats to the health and eco- nomic prosperity of mankind. However, the available therapeutic tools for the treatment of most parasitic diseases are extremely limited. Many of them were developed in the first part of this century and are not without risk. The development of parasites resist- ant to many of the available drugs is also responsible for the depressing pic- ture of disease persistence and death. Drug resistance is spreading faster than ever, new drugs are not being developed quickly enough and potential vaccines have so far not fulfilled expectations in field trials. Although alter- native antiparasitic drugs are urgently needed, the response to this crisis is inadequate. The field suffers not so much from a lack of promising scientific approaches, but a lack of funding and commitment from both public sector agencies and the pharmaceutical industry to convert these approaches into new drugs. The past 20 years has witnessed a huge increase in our understanding of the biochemistry, molecular and cell biology of the pathogens that cause these diseases, with attention focused on the characterisation of metabolic path- ways and cell structures that are different between parasite and host. The advent of genomics has increased this opportunity and offers a new chal- lenge. Studies on pathogenic bacteria and fungi have already shown the impact that genomic information can have on our level of understanding of such organisms. For example, microarrays describing of the transcription response profile of Mycobacterium tuberculosis have helped to characterise the metabolic pathways of this organism. Coordinated research on the model yeast, Saccharomyces cerevisiae, particularly the methodical knocking out of each gene and characterisation of resultant phenotypes, has shown that it is possible to characterise the role of each gene. Within the next five years, the genome sequences of the parasites that cause malaria, leishmaniasis and trypanosomiasis will be completed and this new data will significantly alter the directions of laboratory research. This expan- sion of molecular and biochemical knowledge will reveal many of the essen- Drugs against parasitic diseases: R&D methodologies and issues • INTRODUCTION 5 tial differences between parasite and host and will open the door to identi- fy metabolic differences that could result in defining potential drug targets. One of the aims of the post-genomic agenda for research on parasites is to provide the
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