Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase.
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.
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts, USA. tkeller@hms.harvard.edu
Tracy L
TL
Keller
Davide
D
Zocco
Mark S
MS
Sundrud
Margaret
M
Hendrick
Maja
M
Edenius
Jinah
J
Yum
Yeon-Jin
YJ
Kim
Hak-Kyo
HK
Lee
Joseph F
JF
Cortese
Dyann F
DF
Wirth
John David
JD
Dignam
Anjana
A
Rao
Chang-Yeol
CY
Yeo
Ralph
R
Mazitschek
Malcolm
M
Whitman
D000604:Amino Acyl-tRNA Synthetases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D052999:Quinazolinones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D058504:Th17 Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism
D004791:Enzyme Inhibitors; D010880:Piperidines; D011799:Quinazolines; D052999:Quinazolinones; C001207:febrifugine; D000604:Amino Acyl-tRNA Synthetases; C415462:glutamyl-prolyl-tRNA synthetase; C010176:halofuginone