Obesity
Protein tyrosine phosphatase (PTP) 1B is a potential therapeutic target for obesity and type 2 diabetes. To investigate how PTP1B affects adiposity, Bence and colleagues generated mice with tissue-specific deletions of Ptp1b in brain, muscle, liver or fat. Only mice lacking neuronal PTP1B were resistant to high-fat diet-induced obesity and were protected from developing leptin resistance. Neuronal PTP1B also regulated adipocyte leptin production and insulin sensitivity independent of changes in body weight. So, it seems for effective obesity and type 2 diabetes therapy, PTP1B inhibitors should be directed to the brain.
Anti-infectives
Infections caused by kinetoplastid protazoan parasites are prevalent in developing countries, but treatments are often toxic. Denny and colleagues identified and characterized a protozoan inositol phosphorylceramide (IPC) synthase, an enzyme essential for the synthesis of cell-membrane sphingolipids. Because this enzyme has no mammalian equivalent, it raises the possibility of developing antiprotozoal drugs with reduced side effects.
Biotechnology
Chang and colleagues have developed a novel method of long-term, systemic therapeutic protein delivery by exploiting the globin-synthesis system in erythroid cells. By targeting human clotting factor IX expression to late-stage erythropoiesis, high-level secretion of clotting factor IX was achieved in a murine model of haemophilia B, resulting in phenotypic correction of the coagulation disorder. Advantages of this method include resistance to transcriptional silencing, induction of immune tolerance and a reduction of the risk of insertional oncogenesis.
Target validation
Current in vitro methods used to study mammalian G-protein-coupled receptor (GPCR)–ligand interactions might not accurately reflect in vivo interactions. Teng and colleagues have developed a simple in vivo method to study and screen GPCR ligands using the nematode Caenorhabditis elegans. In an avoidance assay, C. elegans expressing either mammalian somatostatin-2 receptor (Sstr2) or chemokine-5 receptor in gustatory neurons were able to detect and respond to appropiate agonists. Pre-exposure to ligand led to receptor desensitization and behavioural adaptation, and structure–function relationships could be established for Sstr2 ligands.
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In Brief. Nat Rev Drug Discov 5, 722 (2006). https://doi.org/10.1038/nrd2143
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DOI: https://doi.org/10.1038/nrd2143