Functional genomics: identifying drug targets for parasitic diseases

doi:10.1016/j.pt.2003.09.006

Trends in Parasitology

Volume 19, Issue 11, November 2003, Pages 538-543

https://doi.org/10.1016/j.pt.2003.09.006 Get rights and content

Abstract

The genomic sequences of parasitic diseases are rapidly becoming available and, recently, the full sequence of Plasmodium falciparum has been published. Much has been promised from this genomic revolution including the identification of new drug targets and novel chemotherapeutic treatments for the control of parasitic diseases. The challenge to use this information efficiently will require functional genomics tools such as bioinformatics, microarrays, proteomics and chemical genomics to identify potential drug targets, and to allow the development of optimized lead compounds. The information generated from these tools will provide a crucial link from genomic analysis to drug discovery.

Section snippets

Screening genomes for potential drug targets

The availability of the genome sequences of different parasitic organisms has enabled database mining by using bioinformatic tools to identify biochemical pathways and gene families that are potential drug targets. This can involve the use of comparative bioinformatics to identify single genes or families of genes which encode proteins of known function and which are already considered good drug targets in other organisms. In addition, the identification of genes involved in novel pathways or

Transcriptional profiling, proteomics and chemical genomics

The combination of proteomics with chemical genomics has huge potential to produce lead compounds in a relatively short time period and can enable screening for inhibitors with increased selectivity for the target which should reduce potential side effect problems in the host [16]. The chemical genomics strategy involves the synthesis of chemical libraries of small-molecule compounds that can be used as tools to probe biological mechanisms and to optimize the properties of inhibitors. For

Genetic and chemical validation of potential drug targets

An important aspect for the identification and validation of a drug target is that they should be essential for growth of the organism [25]. Drug target validation represents an efficient way of sorting and prioritizing a large number of candidate genes identified from genome sequences. The target genes can be validated: (i) genetically, by showing that gene disruption and loss-of-function of the protein results in a nonviable or severely disabled parasite; and (ii) chemically, by demonstrating

Drug target – the beginning

The identification of promising novel drug targets is an essential, but a small part of the drug development process [34]. Generating lead compounds from a validated target is a complex process requiring many steps, including appropriate expression of functional protein, assay development for high-throughput screening and secondary assays for lead optimization. Whereas some chemical genomics strategies can help shortcut this process in many cases, it will still be essential [16]. It will also

Public–private partnerships

It is essential that research and development of new chemical entities and novel drug targets against parasitic diseases is encouraged. This obviously requires an economic investment; however, with the low interest of the pharmaceutical industry, it is not clear where the funds necessary to drive the ensuing expansion of activity will be generated [34]. Public–private partnerships have been developed to foster development of vaccines and new drugs against particular diseases. The Medicines for

The future for parasite genomics

The understanding of DNA structure in 1953 by Watson and Crick was a major breakthrough that heralded the era of the gene and revolutionized biology. The rapidly expanding list of full genome sequences holds similar promise and, already, the advent of applied genomic technologies (functional genomics) has initiated several new fields of research and promises the development of new treatments for important diseases. This expectation is certainly evident for parasitic infectious diseases, and

Acknowledgements

The work from our laboratories described in this article was supported by the National Health and Medical Research Council of Australia, Wellcome Trust, UK and the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR). We thank Marian Cravino for preparation of figures, and Susanne Miller and Rob Good for contributing the data presented. A.F.C. and B.S.C. are Howard Hughes International Scholar.

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Trends in Parasitology

Functional genomics: identifying drug targets for parasitic diseases

Abstract

Section snippets

Screening genomes for potential drug targets

Transcriptional profiling, proteomics and chemical genomics

Genetic and chemical validation of potential drug targets

Drug target – the beginning

Public–private partnerships

The future for parasite genomics

Acknowledgements

Trends Parasitol.

Drug Resist. Updat.

Trends Microbiol.

Curr. Opin. Microbiol.

Lancet

Trends Parasitol.

Trends Microbiol.

J. Biol. Chem.

Mol. Biochem. Parasitol.

Drug Resist. Updat.

Exp. Parasitol.

Parasitol. Int.

Lancet

J. Biol. Chem.

J. Biol. Chem.

Genome sequence of the human malaria parasite Plasmodium falciparum

Nature

The cell biology of parasitism in Trypanosoma brucei: insights and drug targets from genomic approaches?

Curr. Pharm. Des.

Research and development costs for new drugs by therapeutic category. A study of the US pharmaceutical industry

Pharmacoeconomics

Dissecting apicoplast targeting in the malaria parasite Plasmodium falciparum

Science

A type II pathway for fatty acid biosynthesis presents drug targets in Plasmodium falciparum

Antimicrob. Agents Chemother.