Metabolomics in drug target discovery.
ABSTRACT Most diseases result in metabolic changes. In many cases, these changes play a causative role in disease progression. By identifying pathological metabolic changes, metabolomics can point to potential new sites for therapeutic intervention. Particularly promising enzymatic targets are those that carry increased flux in the disease state. Definitive assessment of flux requires the use of isotope tracers. Here we present techniques for finding new drug targets using metabolomics and isotope tracers. The utility of these methods is exemplified in the study of three different viral pathogens. For influenza A and herpes simplex virus, metabolomic analysis of infected versus mock-infected cells revealed dramatic concentration changes around the current antiviral target enzymes. Similar analysis of human-cytomegalovirus-infected cells, however, found the greatest changes in a region of metabolism unrelated to the current antiviral target. Instead, it pointed to the tricarboxylic acid (TCA) cycle and its efflux to feed fatty acid biosynthesis as a potential preferred target. Isotope tracer studies revealed that cytomegalovirus greatly increases flux through the key fatty acid metabolic enzyme acetyl-coenzyme A carboxylase. Inhibition of this enzyme blocks human cytomegalovirus replication. Examples where metabolomics has contributed to identification of anticancer drug targets are also discussed. Eventual proof of the value of metabolomics as a drug target discovery strategy will be successful clinical development of therapeutics hitting these new targets.
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ABSTRACT: Metabolites, the chemical entities that are transformed during metabolism, provide a functional readout of cellular biochemistry. With emerging technologies in mass spectrometry, thousands of metabolites can now be quantitatively measured from minimal amounts of biological material, which has thereby enabled systems-level analyses. By performing global metabolite profiling, also known as untargeted metabolomics, new discoveries linking cellular pathways to biological mechanism are being revealed and are shaping our understanding of cell biology, physiology and medicine.Nature Reviews Molecular Cell Biology 01/2012; 13(4):263-9. · 37.16 Impact Factor
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ABSTRACT: Emerging evidence highlights a critical role for protein acetylation during herpesvirus infection. As prominent modulators of protein acetylation, histone deacetylases (HDACs) are essential transcriptional and epigenetic regulators. Not surprisingly, viruses have evolved a wide array of mechanisms to subvert HDAC functions. Here, we review the mechanisms underlying HDAC regulation during herpesvirus infection. We next discuss the roles of acetylation in host defense against herpesvirus infection. Finally, we provide a perspective on the contribution of current mass spectrometry-based "omic" technologies to infectious disease research, offering a systems biology view of infection.Viruses 01/2013; 5(7):1607-1632. · 2.51 Impact Factor
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ABSTRACT: As obligate intracellular parasites viruses rely on host cell factors and functions for all stages of infection, from entry to spread. Characterization of these cellular components is critical to advance our understanding of the infection process and develop novel means to combat viral pathogens. To this end, the recent application of next generation approaches including compound screening, cell-targeting RNA interference, gene knockouts, and several proteomics approaches has served to expand our understanding of virus-host interactions, and facilitated the discovery of potential anti-viral targets. Here we review recent progress in the use of these next generation approaches and discuss their challenges, pitfalls, and potential applications for the study of virus-host interplay.Current opinion in virology. 11/2013; 4C:8-14.