Trends in Parasitology
Volume 29, Issue 12, December 2013, Pages 603-611
Journal home page for Trends in Parasitology

Review
Chemical genomics for studying parasite gene function and interaction

https://doi.org/10.1016/j.pt.2013.10.005Get rights and content

Highlights

  • Quantitative high-throughput screen (qHTS) of small molecules (SMs).

  • SMs as a tool for studying phenotypes and gene function.

  • Combination of SM screening and genome-wide approaches.

  • Target identification and pathway/network building.

With the development of new technologies in genome sequencing, gene expression profiling, genotyping, and high-throughput screening of chemical compound libraries, small molecules are playing increasingly important roles in studying gene expression regulation, gene–gene interaction, and gene function. Here we briefly review and discuss some recent advancements in drug target identification and phenotype characterization using combinations of high-throughput screening of small-molecule libraries and various genome-wide methods such as whole-genome sequencing, genome-wide association studies (GWAS), and genome-wide expression analysis. These approaches can be used to search for new drugs against parasite infections, to identify drug targets or drug resistance genes, and to infer gene function.

Section snippets

What is meant by chemical genomics?

Chemical genomics is a means to study biology by recapitulating the effect of changes in gene integrity (e.g., mutations) and chromatin structure (e.g., epigenetic gene regulation) through the pharmacologic effect of a small molecule (SM) 1, 2. Effects elicited by SMs can take place either through direct interaction with a target protein, or indirectly by modulating expression or post-transcriptional/translational modification [2]. Experimentally, a cell line(s) is treated with various SMs and

SMs as tools for phenotypic screens

Changes in a genome can have different effects on a cell. Phenotypic differences between individual parts of an organism are largely controlled by differences in their genomic DNA. Genetic variations such as nucleotide substitution, insertion/deletion (indel), copy-number variation (CNV), and epigenetic modifications likely affect cell growth or survival to some degree. At the molecular level, if a change occurs in the coding region of a gene, the change may alter protein structure or enzyme

High-throughput screening (HTS) and genome-wide approaches to study targets of SMs

Most bioactive SMs carry out their pharmacologic action through binding to protein targets. Therefore, identification of protein targets is important in our understanding of the mode of action and the mechanisms underlying SM efficacy. Various biochemical approaches such as photo-crosslinking, radioisotope labeling, and affinity chromatography have been used to identify SM targets [16]; however, these methods are labor-intensive, time-consuming, and often generate inconclusive experimental

Concluding remarks and future perspectives

The ultimate goal of chemical genomics is to link variations in the genome to differences in cell survival, growth, and differentiation. Although it will be difficult to detect mutations that are essential for cell survival, many nonessential but important genetic variations can be identified through chemical genomics approaches. If a sufficiently diverse array of pharmacologically active SMs are screened against a large number of cell lines or microbes, it is possible to build connections or

Acknowledgments

This work was supported by the National Natural Science Foundation of China (grants 81220108019, 81271858, and 81201324), by Project 111 of the State Bureau of Foreign Experts and Ministry of Education of China (B06016), and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Center for Advancing Translational Sciences, National Institutes of Health. We thank Dr Ronald Johnson for comments, and intramural editor Brenda Rae Marshall

References (101)

  • A. Moller

    Two-dimensional gel electrophoresis: a powerful method to elucidate cellular responses to toxic compounds

    Toxicology

    (2001)
  • E.F. Petricoin et al.

    SELDI-TOF-based serum proteomic pattern diagnostics for early detection of cancer

    Curr. Opin. Biotechnol.

    (2004)
  • K.L. Olszewski

    Host–parasite interactions revealed by Plasmodium falciparum metabolomics

    Cell Host Microbe

    (2009)
  • Z. Herceg et al.

    Genetic and epigenetic alterations as biomarkers for cancer detection, diagnosis and prognosis

    Mol. Oncol.

    (2007)
  • D.K. Pokholok

    Genome-wide map of nucleosome acetylation and methylation in yeast

    Cell

    (2005)
  • A. Barski

    High-resolution profiling of histone methylations in the human genome

    Cell

    (2007)
  • B. Sadikovic

    Genome-wide H3K9 histone acetylation profiles are altered in benzopyrene-treated MCF7 breast cancer cells

    J. Biol. Chem.

    (2008)
  • L.M. Mayr et al.

    Novel trends in high-throughput screening

    Curr. Opin. Pharmacol.

    (2009)
  • N. Thorne

    Apparent activity in high-throughput screening: origins of compound-dependent assay interference

    Curr. Opin. Chem. Biol.

    (2010)
  • S. Draghici

    Reliability and reproducibility issues in DNA microarray measurements

    Trends Genet.

    (2006)
  • T. Roemer

    Bugs, drugs and chemical genomics

    Nat. Chem. Biol.

    (2012)
  • P. Hou

    Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds

    Science

    (2013)
  • E.R. Sharlow

    A target-based high throughput screen yields Trypanosoma brucei hexokinase small molecule inhibitors with antiparasitic activity

    PLoS Negl. Trop. Dis.

    (2010)
  • J.L. Siqueira-Neto

    Antileishmanial high-throughput drug screening reveals drug candidates with new scaffolds

    PLoS Negl. Trop. Dis.

    (2010)
  • W.A. Guiguemde

    Chemical genetics of Plasmodium falciparum

    Nature

    (2010)
  • J. Yuan

    Chemical genomic profiling for antimalarial therapies, response signatures, and molecular targets

    Science

    (2011)
  • S. Meister

    Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery

    Science

    (2011)
  • J.A. Frearson

    N-myristoyltransferase inhibitors as new leads to treat sleeping sickness

    Nature

    (2010)
  • L. Norambuena

    Chemical genomics approaches in plant biology

    Methods Mol. Biol.

    (2009)
  • E. Ullu

    RNA interference in protozoan parasites

    Cell. Microbiol.

    (2004)
  • T.A. Hawkins

    The small molecule Mek1/2 inhibitor U0126 disrupts the chordamesoderm to notochord transition in zebrafish

    BMC Dev. Biol.

    (2008)
  • U. Scherf

    A gene expression database for the molecular pharmacology of cancer

    Nat. Genet.

    (2000)
  • D.A. Wolters

    An automated multidimensional protein identification technology for shotgun proteomics

    Anal. Chem.

    (2001)
  • M.P. Washburn

    Large-scale analysis of the yeast proteome by multidimensional protein identification technology

    Nat. Biotechnol.

    (2001)
  • H. Ovaa et al.

    Chemical biology approaches to probe the proteome

    Chembiochem

    (2008)
  • U. Rix et al.

    Target profiling of small molecules by chemical proteomics

    Nat. Chem. Biol.

    (2009)
  • M.D. Urbaniak

    Chemical proteomic analysis reveals the drugability of the kinome of Trypanosoma brucei

    ACS Chem. Biol.

    (2012)
  • L.D. Roberts

    Metabolic phenotyping of a model of adipocyte differentiation

    Physiol. Genomics

    (2009)
  • J. Han

    Metabolomics: towards understanding host–microbe interactions

    Future Microbiol.

    (2010)
  • Z. Wang

    Combinatorial patterns of histone acetylations and methylations in the human genome

    Nat. Genet.

    (2008)
  • D.T. Ross

    Systematic variation in gene expression patterns in human cancer cell lines

    Nat. Genet.

    (2000)
  • N. Nakatsu

    Chemosensitivity profile of cancer cell lines and identification of genes determining chemosensitivity by an integrated bioinformatical approach using cDNA arrays

    Mol. Cancer Ther.

    (2005)
  • S.A. Amundson

    Integrating global gene expression and radiation survival parameters across the 60 cell lines of the National Cancer Institute Anticancer Drug Screen

    Cancer Res.

    (2008)
  • T. Nakamura

    Identification of candidate genes determining chemosensitivity to anti-cancer drugs of gastric cancer cell lines

    Biol. Pharm. Bull.

    (2009)
  • H. Jiang

    Genome-wide compensatory changes accompany drug-selected mutations in the Plasmodium falciparum crt gene

    PLoS ONE

    (2008)
  • K. Ganesan

    A genetically hard-wired metabolic transcriptome in Plasmodium falciparum fails to mount protective responses to lethal antifolates

    PLoS Pathog.

    (2008)
  • A.F. Cowman

    Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum

    Proc. Natl. Acad. Sci. U.S.A.

    (1988)
  • D.S. Peterson

    Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum malaria

    Proc. Natl. Acad. Sci. U.S.A.

    (1990)
  • J. Yuan

    Genetic mapping of targets mediating differential chemical phenotypes in Plasmodium falciparum

    Nat. Chem. Biol.

    (2009)
  • G. Hu

    Transcriptional profiling of growth perturbations of the human malaria parasite Plasmodium falciparum

    Nat. Biotechnol.

    (2009)
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