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Biological Chemistry

Chemists Stabilize Spliceostatins

Engineered bacterium produces more stable versions of natural products that show promising anticancer activity

by Stephen K. Ritter
August 25, 2014 | APPEARED IN VOLUME 92, ISSUE 34

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By reprogramming a microbe, Pfizer scientists have developed a biosynthetic pathway for making more stable versions of spliceostatins, a class of compounds with promising anticancer activity (Proc. Natl. Acad. Sci. USA 2014, DOI: 10.1073/pnas.1408300111). Spliceostatins are natural products that inhibit actions of the spliceosome, a protein-RNA hybrid complex responsible for editing mRNA before the ribosome uses it to make proteins. Researchers have discovered that misregulation of mRNA splicing and mutations in the splicing machinery are associated with several cancers and that spliceostatins can put a halt to the problems. However, the parent spliceostatin contains an unstable hemiketal group that has prevented it from advancing as a drug candidate. Pfizer’s Alessandra S. Eustáquio and her colleagues identified a dioxygenase enzyme responsible for the hemiketal biosynthesis and deleted the corresponding gene from a Burkholderia bacterium. The engineered microbe exclusively produces spliceostatin analogs with a carboxylic acid group rather than the hemiketal group, which are as active as the original spliceostatin but much more stable. The team is now working to increase production of the spliceostatin shown for further study.

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