Metabolomics in Drug Target Discovery

Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA.
Cold Spring Harbor Symposia on Quantitative Biology 11/2011; 76:235-46. DOI: 10.1101/sqb.2011.76.010694
Source: PubMed


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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    • "Interestingly, both PYC and ACC require biotin as cofactor, with this vitamin donating a carboxyl anion to the very specific organic acid substrate [45] [57]. There is limited information on PYC in the metabolomics literature, but ACC has been the subject of more metabolic research due to it potentially serving as an antibiotic drug target, which Rabinowitz and coworkers [58] illustrated using isotope tracer metabolites and a metabolomics research approach. Additional metabolomics-related approaches by de Carvalho et al. [19] pertaining to these genes associated with fatty acids revealed compartmentalized cocatabolism of carbon substrates in M. tuberculosis and a description of how various carbohydrates and fatty acids can be channeled simultaneously to their respective metabolic fates. "
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