Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase.

Nature Chemical Biology
Tracy KellerMalcolm Whitman

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.

References

Jan 1, 1973·Advances in Pharmacology and Chemotherapy·J F Ryley, M J Betts
Apr 2, 1998·General Pharmacology·M Pines, A Nagler
Aug 31, 2000·Annual Review of Biochemistry·M Ibba, D Soll
Oct 25, 2001·The Journal of Organic Chemistry·Shū KobayashiYusuke Wataya
May 31, 2002·Journal of Medicinal Chemistry·Haruhisa KikuchiYoshiteru Oshima
Dec 17, 2002·Autoimmunity·Tracy McGahaConstantin Bona
Jul 19, 2003·Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation·Mark PinesArnon Nagler
Dec 17, 2004·Nature·Jon Clardy, Christopher Walsh
May 12, 2005·The Journal of Biological Chemistry·Benfang Ruan, Dieter Söll
Jul 14, 2005·Annual Review of Nutrition·M S KilbergV Leung-Pineda
Aug 2, 2005·Nature Reviews. Immunology·Vincenzo Bronte, Paola Zanovello
Sep 25, 2007·Molecular Cell·Jeffrey A PleissChristine Guthrie
Sep 28, 2007·European Journal of Immunology·Teresa ZelanteLuigina Romani
Jan 9, 2008·The Journal of Biological Chemistry·Kathryn E SplanKarin Musier-Forsyth
May 6, 2008·Cell·Konrad T Howitz, David A Sinclair
May 24, 2008·Science·Yasemin SancakDavid M Sabatini
Jun 27, 2008·Proceedings of the National Academy of Sciences of the United States of America·David PlouffeElizabeth A Winzeler
Nov 26, 2008·Nature Reviews. Immunology·Gökhan S Hotamisligil, Ebru Erbay
Jun 6, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Narender NathShailendra Giri
Jun 19, 2009·Trends in Biochemical Sciences·Rupak MukhopadhyayPaul L Fox
Jul 2, 2009·Proceedings of the National Academy of Sciences of the United States of America·Stephen P CobboldHerman Waldmann
Dec 17, 2009·Trends in Endocrinology and Metabolism : TEM·Rozalyn M Anderson, Richard Weindruch
Dec 19, 2009·The American Journal of Pathology·Kjetil Boye, Gunhild M Maelandsmo
Apr 7, 2010·International Reviews of Immunology·Lei HuangAndrew L Mellor
Apr 17, 2010·Science·Luigi FontanaValter D Longo
Jul 20, 2010·Immunological Reviews·Ursula Grohmann, Vincenzo Bronte
Oct 23, 2010·Molecular Cell·Marcia C Haigis, Bruce A Yankner
Nov 12, 2010·Journal of Acquired Immune Deficiency Syndromes : JAIDS·Henry B KoonSusan E Krown
Dec 16, 2010·Nature Reviews. Molecular Cell Biology·Roberto ZoncuDavid M Sabatini
Jan 15, 2011·Nature Reviews. Immunology·David Finlay, Doreen A Cantrell
Apr 20, 2011·Journal of the American Academy of Dermatology·Dagmar von BubnoffClaudia Wickenhauser

❮ Previous
Next ❯

Citations

May 1, 2012·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Randolph M NesseGilbert S Omenn
Feb 26, 2014·European Journal of Medicinal Chemistry·Haruhisa KikuchiYoshiteru Oshima
Feb 22, 2013·EMBO Molecular Medicine·Peng Yao, Paul L Fox
Jul 23, 2014·Journal of Structural and Functional Genomics·Vitul JainManickam Yogavel
Dec 7, 2013·Current Opinion in Oncology·Lei Huang, Andrew L Mellor
Oct 7, 2015·Journal of Industrial Microbiology & Biotechnology·Esther K SchmittP Krastel
Aug 22, 2015·European Journal of Medicinal Chemistry·Sofia A SantosAlexandra Paulo
Aug 12, 2015·Proceedings of the National Academy of Sciences of the United States of America·Buvana RavishankarTracy L McGaha
Jan 21, 2016·The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation·Hisashi OishiShaf Keshavjee
Oct 30, 2012·Trends in Immunology·David H Munn, Andrew L Mellor
Oct 11, 2015·Biochimica Et Biophysica Acta·Hila Barzilai-TutschOrna Halevy
Mar 11, 2016·Bioengineered·Adélaïde Saint-LégerLluís Ribas de Pouplana
Apr 5, 2013·Immunological Reviews·Pavel Ivanov, Paul Anderson
Aug 15, 2012·Immunological Reviews·Tracy L McGahaAndrew L Mellor
Mar 29, 2014·Journal of Cellular Physiology·Jiaqi LiuAndrew Leask
Sep 5, 2015·Nature Reviews. Drug Discovery·Carmel B NanthakumarSimon J F Macdonald
Jul 4, 2015·Pigment Cell & Melanoma Research·Gregory R Kardos, Gavin P Robertson
Apr 16, 2014·Biochimica Et Biophysica Acta·Beatriz A CastilhoEvelyn Sattlegger
Nov 14, 2014·The Biochemical Journal·Arvind Sharma, Amit Sharma
May 21, 2013·International Immunopharmacology·Tony L H ChuCaigan Du
May 23, 2015·Science Translational Medicine·Jonathan D HermanRalph Mazitschek
Nov 19, 2013·Seminars in Immunology·Mark S Sundrud, Catherine Trivigno
Mar 7, 2014·International Journal for Parasitology. Drugs and Drug Resistance·James S PhamStuart A Ralph
Jun 14, 2013·Nucleic Acids Research·Cédric OrelleAlexander S Mankin
May 20, 2016·Annual Review of Pathology·Sean P ColganDouglas J Kominsky
May 24, 2016·Cell Systems·Daniel J O'ConnellRamnik J Xavier
Aug 17, 2016·Trends in Parasitology·Saman HabibKirti Gupta

❮ Previous
Next ❯

Methods Mentioned

BETA
ELISA
FACS

Software Mentioned

FlowJo
Prism

Related Concepts

Related Feeds

Antimalarial Agents (ASM)

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

Antimalarial Agents

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

Autoimmune Diseases

Autoimmune diseases occur as a result of an attack by the immune system on the body’s own tissues resulting in damage and dysfunction. There are different types of autoimmune diseases, in which there is a complex and unknown interaction between genetics and the environment. Discover the latest research on autoimmune diseases here.