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 TH 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.
Original language | English |
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Pages (from-to) | 311-317 |
Number of pages | 7 |
Journal | Nature Chemical Biology |
Volume | 8 |
Issue number | 3 |
DOIs | |
State | Published - Mar 2012 |
Bibliographical note
Funding Information:The authors would like to thank R. Copeland (Epizyme) for advice on the execution of tight-binding analysis, W. Kuo Harvard Catalyst Laboratory for Innovative Translational Technologies for assistance with the establishment of qPCR assays, and C. Walsh (Harvard), T. Roberts (Dana-Farber Cancer Institute) and S. Thomas (National Institute of Environmental Health Science, USA) for their valuable comments on the manuscript. This work was supported by US National Institutes of Health (NIH) grant GM089885 and a Harvard Technology Accelerator Award (to M.W.); by grants PJ00812701 and PJ008196 from The Next Generation BioGreen 21 Program, Rural Development Administration, Republic of Korea (to C.Y.Y. and H.K.L.); and by NIH grants AI40127 and AI48213 and Juvenile Diabetes Research Foundation 17-2010-421 (to A.R.).