2. Academic Validation
  3. The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs

The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs

  • Sci Transl Med. 2015 May 20;7(288):288ra77. doi: 10.1126/scitranslmed.aaa3575.
Jonathan D Herman 1,  Lauren R Pepper 2,  Joseph F Cortese 3,  Guillermina Estiu 4,  Kevin Galinsky 3,  Vanessa Zuzarte-Luis 5,  Emily R Derbyshire 6,  Ulf Ribacke 7,  Amanda K Lukens 8,  Sofia A Santos 9,  Vishal Patel 6,  Clary B Clish 3,  William J Sullivan Jr 10,  Huihao Zhou 11,  Selina E Bopp 7,  Paul Schimmel 12,  Susan Lindquist 13,  Jon Clardy 14,  Maria M Mota 5,  Tracy L Keller 15,  Malcolm Whitman 15,  Olaf Wiest 16,  Dyann F Wirth 17,  Ralph Mazitschek 18
Affiliations

Affiliations

  • 1 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.
  • 2 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • 3 Infectious Diseases Program, Broad Institute, Cambridge, MA 02142, USA.
  • 4 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.
  • 5 Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa,1649-028 Lisbon, Portugal.
  • 6 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 7 Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
  • 8 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.
  • 9 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.
  • 10 Departments of Pharmacology and Toxicology and Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 11 Department of Molecular Biology, Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • 12 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.
  • 13 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA.
  • 14 Infectious Diseases Program, Broad Institute, Cambridge, MA 02142, USA. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 15 Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
  • 16 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.
  • 17 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.
  • 18 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.
PMID: 25995223 DOI: 10.1126/scitranslmed.aaa3575
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.

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