178 Current Drug Targets, 2009, 10, 178-192 1389-4501/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd. Current Treatment and Drug Discovery Against Leishmania spp. and Plasmodium spp.: A Review Angela Kaysel Cruz 1, * , Juliano Simões de Toledo 1 , Mofolusho Falade 2 , Mônica Cristina Terrão 1 , Sumalee Kamchonwongpaisan 2 , Dennis E. Kyle 3 and Chairat Uthaipibull 2 1 Department of Cell and Molecular Biology and Pathogens, School of Medicine, University of São Paulo at Ribeirão Preto, Av Bandeirantes, 3900, 14049900, São Paulo, Brazil; 2 Protein-Ligand Engineering and Molecular Biology Labo- ratory, National Center for Genetic Engineering and Biotechnology, 113 Thailand Science Park, Phaholyothin Road, Klong 1, Klong Luang, Pathumthani 12120 Thailand and 3 Department of Global Health, College of Public Health, Uni- versity of South Florida, 3720 Spectrum Blvd, Suite 304, Tampa, FL 33612, USA Abstract: Malaria and leishmaniasis are the most prevalent tropical diseases caused by protozoan parasites. Half of world’s population is at risk of malaria and more than 2 million of new cases of leishmaniasis occur annually. There are no vaccines available for these diseases and current treatments suffer from several limitations. Therefore, novel drugs for malaria and leishmaniasis are much-needed. This article reviews the agents currently in use for treatment of these dis- eases, their known mechanisms of action and weaknesses. We present an overview of the main strategies for drug discov- ery and the relevance of these parasites genomics/proteomics data for a rational search of molecular targets and matching leads. In this direction, we emphasize the importance of the highly integrated partnerships and networks between scientists in academic institutions and industry involving several countries that promise to increase the chances of success and en- hance cost-effectiveness in drug discovery against these parasitic diseases. In addition, we approach the available assays for testing lead compounds in large scale and their limitations for they represent one of the bottlenecks in the pipeline for novel drug discovery. We conclude the article presenting a recent coordinated initiative (TDR Transfection Network) es- tablished to overcome some of these limitations by the generation of Plasmodium and Leishmania transgenic parasites better suited for HTS platforms. Key Words: Leishmaniasis, malaria, chemotherapy, drug discovery, molecular targets. 1. LEISHMANIASIS AND MALARIA EPIDEMIOL- OGY The World Health Organization (WHO) estimates that one sixth of the world's population is suffering from ne- glected tropical diseases [1]. The precarious life conditions, the social disorganization and the lack of an effective politi- cal action and educational programs contribute to persistence of these diseases in the poorest regions of the world. Malaria and leishmaniasis are the most prevalent neglected diseases caused by protozoan parasites. Half of world’s population is at risk of malaria. More than 500 million of people become severely ill with nearly a million people die due to plasmo- dium infection every year. Currently, leishmaniasis threatens 350 million of people around the world; more than 2 million of new cases of leishmaniasis occur annually (http://www. who.int/tdr/diseases/leish/diseaseinfo.htm). Brazil, India, Bangladesh and Sudan present 90% of cases of visceral leishmaniasis around the world. According to WHO, in the last two decades the number of cases of leishmaniasis in- creased due to the widening of endemic areas and the emer- *Address correspondence to this author at the Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes, no. 3900, CEP 14049-900 Ribeirão Preto, SP, Brazil; Tel: +55 16 3602 3318; Fax: +55 l6 3633 1786; E-mail: akcruz@fmrp.usp.br gence of new focus of leishmaniasis. Epidemiological stud- ies indicate that deforesting, unsettled growth of urban cen- ters and changing habits of the insect vector are contributing to disease urbanization and new endemic foci [2-4]. Seventeen Leishmania species known to infect humans are distributed in 88 countries around the world. In Brazil, among the 14 species of Leishmania identified 10 are known to infect human beings. Depending on several factors, which includes the species of Leishmania and the host immune response, the pathology caused by Leishmania can vary from asymptomatic and mild cutaneous self-healing forms, diffuse cutaneous leishmaniasis, or the mucosal form of the disease, to the severe visceral (or Kala-azar) leishmaniasis, which is fatal if not treated [5-8]. Malaria remains a public health problem of enormous magnitude in tropical and subtropical regions of the world: WHO estimates the number of new cases annually to be about 247 million from about 3.3 billion people at risk. Of these, nearly a million deaths occur, mostly in children under the age of 5 and pregnant women. The population exposed to the risk of this pernicious infection extends from Africa, where the greatest burden exists, Southeast Asia, Papua New Guinea and South America. The burden of infection is high- est in sub-Saharan Africa owing to poverty and poor health- care. In these highly affected areas, the majority of hospital