Selection of Molecular Targets for Drug Development Against Trypanosomatids
Trypanosomatid parasites are a group of flagellated protozoa that includes the genera Leishmania and Trypanosoma, which are the causative agents of diseases (leishmaniases, sleeping sickness and Chagas disease) that cause considerable morbidity and mortal
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Selection of Molecular Targets for Drug Development Against Trypanosomatids Despina Smirlis and Milena Botelho Pereira Soares
Abstract Trypanosomatid parasites are a group of flagellated protozoa that includes the genera Leishmania and Trypanosoma, which are the causative agents of diseases (leishmaniases, sleeping sickness and Chagas disease) that cause considerable morbidity and mortality, affecting more than 27 million people worldwide. Today no effective vaccines for the prevention of these diseases exist, whereas current chemotherapy is ineffective, mainly due to toxic side effects of current drugs and to the emergence of drug resistance and lack of cost effectiveness. For these reasons, rational drug design and the search of good candidate drug targets is of prime importance. The search for drug targets requires a multidisciplinary approach. To this end, the completion of the genome project of many trypanosomatid species gives a vast amount of new information that can be exploited for the identification of good drug candidates with a prediction of “druggability” and divergence from mammalian host proteins. In addition, an important aspect in the search for good drug targets is the “target identification” and evaluation in a biological pathway, as well as the essentiality of the gene in the mammalian stage of the parasite, which is provided by basic research and genetic and proteomic approaches. In this chapter we will discuss how these bioinformatic tools and experimental evaluations can be integrated for the selection of candidate drug targets, and give examples of metabolic and signaling pathways in the parasitic protozoa that can be exploited for rational drug design.
D. Smirlis (*) Hellenic Pasteur Institute, Athens, Greece e-mail: [email protected] M.B.P. Soares Gonçalo Moniz Research Center, Oswaldo Cruz Foundation, Salvador, Bahia, Brazil Center of Biotechnology and Cell Therapy, Hospital São Rafael, Salvador, Bahia, Brazil e-mail: [email protected] A.L.S. Santos et al. (eds.), Proteins and Proteomics of Leishmania and Trypanosoma, Subcellular Biochemistry 74, DOI 10.1007/978-94-007-7305-9_2, © Springer Science+Business Media Dordrecht 2014
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D. Smirlis and M.B.P. Soares
Abbreviations AK ALD APRT CatB CDK CNS CPA CPB CRK CYC CYP51 DHFR ECK1 ENO G3DPH GD3DPH GK GSH GSK-3 GSpS HAT HGPRT HK kDNA MPK PFK PGI PGK PGM PK POS PTR PYK SMT SQS STE7 TPI TryR TryS TS TXN WHO XPRT
Adenosine kinase Fructose 1,6 aldolase Adenine phopsphoribosyltransferase Cathepsin B Cyclin dependent kinase Central Nervous System Cysteine proteinase A Cysteine proteinase B cdc2 related kinase Cyclin Cytochrome P-450 51 Dihydrofolate reductase ERK-like, CRK-like Kinase-1 Enolase Glycerol-3-phosphate dehydrogenase Glyceraldehyde 3-phosphate dehydrogenase Glycerol kinase Glutathione Glycogen synthase kinase 3 Glutathionylspermidine Human African trypanosomiasis Hypoxanthine guanine phopsphoribosyltransferase Hexokinase Kinetoplast DNA Mitogen activated kinase Phosphofructose kinase Phosphoglucose isomerase Phosphoglyce
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