title: The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs.
abstract: The emergence of drug resistance is a major limitation of current antimalarials. The discovery of new druggable targets and pathways including those that are critical for multiple life cycle stages of the malaria parasite is a major goal for developing next-generation antimalarial drugs. Using an integrated chemogenomics approach that combined drug resistance selection, whole-genome sequencing, and an orthogonal yeast model, we demonstrate that the cytoplasmic prolyl-tRNA (transfer RNA) synthetase (PfcPRS) of the malaria parasite Plasmodium falciparum is a biochemical and functional target of febrifugine and its synthetic derivative halofuginone. Febrifugine is the active principle of a traditional Chinese herbal remedy for malaria. We show that treatment with febrifugine derivatives activated the amino acid starvation response in both P. falciparum and a transgenic yeast strain expressing PfcPRS. We further demonstrate in the Plasmodium berghei mouse model of malaria that halofuginol, a new halofuginone analog that we developed, is active against both liver and asexual blood stages of the malaria parasite. Halofuginol, unlike halofuginone and febrifugine, is well tolerated at efficacious doses and represents a promising lead for the development of dual-stage next-generation antimalarials.
authors.affiliation: Infectious Diseases Program, Broad Institute, Cambridge, MA 02142, USA. Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Biological and Biomedical Sciences, Boston, MA 02115, USA. Harvard/Massachusetts Institute of Technology (MIT) Division of Health Sciences and Technology, Boston, MA 02115, USA. Harvard/MIT MD-PhD Program, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Herman
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Lauren R
authors.initials: LR
authors.lastname: Pepper
authors.affiliation: Infectious Diseases Program, Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cortese
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA. Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Guillermina
authors.initials: G
authors.lastname: Estiu
authors.affiliation: Infectious Diseases Program, Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Galinsky
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa,1649-028 Lisbon, Portugal.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Zuzarte-Luis
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Derbyshire
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Ulf
authors.initials: U
authors.lastname: Ribacke
authors.affiliation: Infectious Diseases Program, Broad Institute, Cambridge, MA 02142, USA. Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Lukens
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA. Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Professor Gama Pinto, Lisbon 1640-003, Portugal.
authors.forename: Sofia A
authors.initials: SA
authors.lastname: Santos
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Vishal
authors.initials: V
authors.lastname: Patel
authors.affiliation: Infectious Diseases Program, Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.affiliation: Departments of Pharmacology and Toxicology and Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Sullivan
authors.affiliation: Department of Molecular Biology, Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Huihao
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Selina E
authors.initials: SE
authors.lastname: Bopp
authors.affiliation: Department of Molecular Biology, Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. The Scripps Research Institute, Florida, Jupiter, FL 33458, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Schimmel
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
authors.affiliation: Infectious Diseases Program, Broad Institute, Cambridge, MA 02142, USA. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Clardy
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa,1649-028 Lisbon, Portugal.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mota
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Keller
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Whitman
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA. Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA. School of Chemical Biology and Biotechnology, Laboratory for Computational Chemistry and Drug Design, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
authors.forename: Olaf
authors.initials: O
authors.lastname: Wiest
authors.affiliation: Infectious Diseases Program, Broad Institute, Cambridge, MA 02142, USA. Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. rmazitschek@mgh.harvard.edu dfwirth@hsph.harvard.edu.
authors.forename: Dyann F
authors.initials: DF
authors.lastname: Wirth
authors.affiliation: Infectious Diseases Program, Broad Institute, Cambridge, MA 02142, USA. Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA. rmazitschek@mgh.harvard.edu dfwirth@hsph.harvard.edu.
authors.forename: Ralph
authors.initials: R
authors.lastname: Mazitschek
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D017076:Computer-Aided Design; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004912:Erythrocytes / Q000469:parasitology; D008099:Liver / Q000469:parasitology; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D052999:Quinazolinones / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D010880:Piperidines; D015800:Protozoan Proteins; D011799:Quinazolines; D052999:Quinazolinones; C001207:febrifugine; D000604:Amino Acyl-tRNA Synthetases; C100134:prolyl T RNA synthetase; C010176:halofuginone