From the Harvard School of Dental Mediine: New research by HSDM’s Malcolm Whitman, PhD, a professor of developmental biology, and Tracy Keller, PhD, an instructor in developmental biology, and colleagues may lead to new therapeutic approaches for diseases involving autoimmunity, metabolic signaling, and inflammation. The results of this research were published in the March 2012 issue of Nature Chemical Biology, featured in the HMS/HSDM/HSPH Focus newsletter, and heralded in dozens of news outlets in many languages around the world.
http://www.nature.com/nchembio/journal/v8/n3/full/nchembio.790.html
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 TH17-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.
