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Selection of Molecular Targets for Drug Development Against Trypanosomatids

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Proteins and Proteomics of Leishmania and Trypanosoma

Part of the book series: Subcellular Biochemistry ((SCBI,volume 74))

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.

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Abbreviations

AK:

Adenosine kinase

ALD:

Fructose 1,6 aldolase

APRT:

Adenine phopsphoribosyltransferase

CatB:

Cathepsin B

CDK:

Cyclin dependent kinase

CNS:

Central Nervous System

CPA:

Cysteine proteinase A

CPB:

Cysteine proteinase B

CRK:

cdc2 related kinase

CYC:

Cyclin

CYP51:

Cytochrome P-450 51

DHFR:

Dihydrofolate reductase

ECK1:

ERK-like, CRK-like Kinase-1

ENO:

Enolase

G3DPH:

Glycerol-3-phosphate dehydrogenase

GD3DPH:

Glyceraldehyde 3-phosphate dehydrogenase

GK:

Glycerol kinase

GSH:

Glutathione

GSK-3:

Glycogen synthase kinase 3

GSpS:

Glutathionylspermidine

HAT:

Human African trypanosomiasis

HGPRT:

Hypoxanthine guanine phopsphoribosyltransferase

HK:

Hexokinase

kDNA:

Kinetoplast DNA

MPK:

Mitogen activated kinase

PFK:

Phosphofructose kinase

PGI:

Phosphoglucose isomerase

PGK:

Phosphoglycerate kinase

PGM:

Phosphoglycerate mutase

PK:

Protein kinase

POS:

Posaconazole

PTR:

Pteridine reductase

PYK:

Pyruvate kinase

SMT:

Δ24(15)-sterol methyltransferase

SQS:

Squalene synthatase

STE7:

Signaling terminal 7 extension

TPI:

Triose phosphate isomerase

TryR:

Trypanothione reductase

TryS:

Trypanothione synthatase

TS:

Thymidylate synthase

TXN:

Tryparedoxin

WHO:

World Health Organization

XPRT:

Xanthine phopsphoribosyltransferase

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Acknowledgements

The authors wish to thank the FP7-PEOPLE-2010-IRSES program “ChemBioFight” (Exploring chemical biodiversity with innovative approaches for fighting Chagas and leishmaniasis, grant number 269031) for financial support.

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Authors and Affiliations

  1. Hellenic Pasteur Institute, Athens, Greece

    Despina Smirlis

  2. Gonçalo Moniz Research Center, Oswaldo Cruz Foundation, Salvador, Bahia, Brazil

    Milena Botelho Pereira Soares

  3. Center of Biotechnology and Cell Therapy, Hospital São Rafael, Salvador, Bahia, Brazil

    Milena Botelho Pereira Soares

Authors
  1. Despina Smirlis
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  2. Milena Botelho Pereira Soares
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Correspondence to Despina Smirlis .

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Editors and Affiliations

  1. Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil

    André L.S. Santos

  2. Departamento de Microbiologia Geral, Ins. de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil

    Marta H. Branquinha

  3. Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil

    Claudia M. d’Avila-Levy

  4. Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil

    Lucimar F. Kneipp

  5. Departamento de Biologia Celular e Molecular, Instituto de Biologia Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil

    Cátia L. Sodré

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Smirlis, D., Soares, M.B.P. (2014). Selection of Molecular Targets for Drug Development Against Trypanosomatids. In: Santos, A., Branquinha, M., d’Avila-Levy, C., Kneipp, L., Sodré, C. (eds) Proteins and Proteomics of Leishmania and Trypanosoma. Subcellular Biochemistry, vol 74. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7305-9_2

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