Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase.

Abstract

Febrifugine, the bioactive constituent of one of the 50 fundamental herbs of traditional Chinese medicine, has been characterized for its therapeutic activity, though its molecular target has remained unknown. Febrifugine derivatives have been used to treat malaria, cancer, fibrosis and inflammatory disease. We recently demonstrated that halofuginone (HF), a widely studied derivative of febrifugine, inhibits the development of T(H)17-driven autoimmunity in a mouse model of multiple sclerosis by activating the amino acid response (AAR) pathway. Here we show that HF binds glutamyl-prolyl-tRNA synthetase (EPRS), inhibiting prolyl-tRNA synthetase activity; this inhibition is reversed by the addition of exogenous proline or EPRS. We further show that inhibition of EPRS underlies the broad bioactivities of this family of natural product derivatives. This work both explains the molecular mechanism of a promising family of therapeutics and highlights the AAR pathway as an important drug target for promoting inflammatory resolution.

• Authors: Tracy L Keller, Davide Zocco, Mark S Sundrud, Margaret Hendrick, Maja Edenius, Jinah Yum, Yeon-Jin Kim, Hak-Kyo Lee, Joseph F Cortese, Dyann F Wirth, John David Dignam, Anjana Rao, Chang-Yeol Yeo, Ralph Mazitschek, Malcolm Whitman
• Journal: Nature chemical biology (Nat Chem Biol) Vol. 8 Issue 3 Pg. 311-7 (Feb 12 2012) ISSN: 1552-4469 [Electronic] United States
• PMID: 22327401 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Piperidines
• Quinazolines
• Quinazolinones
• febrifugine
• Amino Acyl-tRNA Synthetases
• glutamyl-prolyl-tRNA synthetase
• halofuginone

Topics

• Amino Acyl-tRNA Synthetases (antagonists & inhibitors, chemistry, metabolism)
• Animals
• Cell Differentiation (drug effects)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemistry, pharmacology)
• Humans
• Mice
• Mice, Inbred C57BL
• Piperidines (chemistry, pharmacology)
• Quinazolines (chemistry, pharmacology)
• Quinazolinones (chemistry, pharmacology)
• Structure-Activity Relationship
• Th17 Cells (drug effects, enzymology, immunology, metabolism)