Discovery of chemically validated malaria liver stage targets

Summary

Principal Investigator: Elizabeth A Winzeler
Abstract: DESCRIPTION (provided by applicant): Because blood stage infections produce most clinical manifestations of malaria, drug development has primarily focused on the development of schizonticides targeting Plasmodium falciparum, the causative agent of the most severe form of human malaria. Increased funding and a growing awareness of the problem of parasite resistance have helped to push a number of new schizonticides into the developmental pipeline and even clinical trials. On the other hand, few of these drug candidates are effective against malaria exoerythrocytic stages, and even fewer are likely to provide a radical cure for P. vivax malaria. The need for drugs which can act as a replacement for primaquine is even more urgent as malaria eradication becomes a higher priority for the world health community. In order to stimulate drug development activity against hepatic stages, more work is needed to understand hepatic stage biology and to discover targets whose activity is essential for both hepatic and blood stage development. I will use a chemical genetic approach to investigate pathways that are critically essential to both blood and hepatic parasite development and then characterize the target(s) revealed by this approach. Specifically, I will grow parasites under sub-lethal concentrations of small molecules with activity against blood and hepatic stage parasites until the parasites acquire low level resistance to the small molecules. I will use genome-scanning to determine the likely target(s). Mutations will be engineered into sensitive parasite strains to prove that they cause resistance. Likely targets will be further characterized using immuno and electron microscopy and localization studies, as well as disruption studies. The work may lead to a better understanding of how to treat tissue stage malaria, provide new antibiotic resistance genes, and provide information about how eukaryotic pathogens become resistant to drugs. PUBLIC HEALTH RELEVANCE: Many antimalarial drugs alleviate symptoms but do not necessarily result in a complete cure because some malaria parasites are able to persist asymptomatically in the liver for months or years. The inability to eliminate cryptic liver forms creates a barrier to malaria eradication. We propose to find new targets that are critical to the liver stages as well as the blood stages with the long term aim of designing better drugs.
Funding Period: 2011-05-06 - 2015-04-30
more information: NIH RePORT

Top Publications

  1. pmc A chemical genomic analysis of decoquinate, a Plasmodium falciparum cytochrome b inhibitor
    Tae Gyu Nam
    Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
    ACS Chem Biol 6:1214-22. 2011
  2. pmc Targeting Plasmodium PI(4)K to eliminate malaria
    Case W McNamara
    1 Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA 2
    Nature 504:248-53. 2013
  3. pmc Antimalarial drug discovery - approaches and progress towards new medicines
    Erika L Flannery
    Department of Pediatrics, University of California San Diego School of Medicine, 9500 Gilman Drive 0741, La Jolla, California 92093, USA
    Nat Rev Microbiol 11:849-62. 2013
  4. pmc Identification of the Plasmodium berghei resistance locus 9 linked to survival on chromosome 9
    Selina E R Bopp
    Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA, USA
    Malar J 12:316. 2013
  5. pmc Using genetic methods to define the targets of compounds with antimalarial activity
    Erika L Flannery
    Department of Pediatrics, University of California, San Diego, School of Medicine, 9500 Gilman Drive 0741, La Jolla, California 92093, United States
    J Med Chem 56:7761-71. 2013
  6. pmc A key role for lipoic acid synthesis during Plasmodium liver stage development
    Brie Falkard
    Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, USA
    Cell Microbiol 15:1585-604. 2013
  7. pmc Na(+) regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials
    Natalie J Spillman
    Research School of Biology, The Australian National University, Canberra, ACT 0200, Australia
    Cell Host Microbe 13:227-37. 2013
  8. pmc Mitotic evolution of Plasmodium falciparum shows a stable core genome but recombination in antigen families
    Selina E R Bopp
    Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California, USA
    PLoS Genet 9:e1003293. 2013
  9. pmc Nuclear repositioning precedes promoter accessibility and is linked to the switching frequency of a Plasmodium falciparum invasion gene
    Bradley I Coleman
    Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA
    Cell Host Microbe 12:739-50. 2012
  10. pmc Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design
    Michael B Harbut
    Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA
    Proc Natl Acad Sci U S A 109:21486-91. 2012

Detail Information

Publications17

  1. pmc A chemical genomic analysis of decoquinate, a Plasmodium falciparum cytochrome b inhibitor
    Tae Gyu Nam
    Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
    ACS Chem Biol 6:1214-22. 2011
    ..The basis for this difference was revealed by molecular docking studies, in which both of these inhibitors were shown to have distinctly different modes of binding within the ubiquinol-binding site of cytochrome b...
  2. pmc Targeting Plasmodium PI(4)K to eliminate malaria
    Case W McNamara
    1 Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA 2
    Nature 504:248-53. 2013
    ..Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria. ..
  3. pmc Antimalarial drug discovery - approaches and progress towards new medicines
    Erika L Flannery
    Department of Pediatrics, University of California San Diego School of Medicine, 9500 Gilman Drive 0741, La Jolla, California 92093, USA
    Nat Rev Microbiol 11:849-62. 2013
    ..In this Review, we discuss the cell-, chemistry- and target-based approaches used to discover new drug candidates that are currently in clinical trials or undergoing preclinical testing. ..
  4. pmc Identification of the Plasmodium berghei resistance locus 9 linked to survival on chromosome 9
    Selina E R Bopp
    Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA, USA
    Malar J 12:316. 2013
    ..As such, the identification of genetic loci associated with susceptibility or resistance may serve to modulate disease severity...
  5. pmc Using genetic methods to define the targets of compounds with antimalarial activity
    Erika L Flannery
    Department of Pediatrics, University of California, San Diego, School of Medicine, 9500 Gilman Drive 0741, La Jolla, California 92093, United States
    J Med Chem 56:7761-71. 2013
    ..Here we discuss how in vitro evolution of drug-resistant strains of Plasmodium falciparum and subsequent whole-genome analysis can be used to find the targets of some of the many compounds discovered in whole-cell phenotypic screens...
  6. pmc A key role for lipoic acid synthesis during Plasmodium liver stage development
    Brie Falkard
    Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, USA
    Cell Microbiol 15:1585-604. 2013
    ..This study also highlights the potential of exploiting lipid metabolism pathways for the design of genetically attenuated sporozoite vaccines. ..
  7. pmc Na(+) regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials
    Natalie J Spillman
    Research School of Biology, The Australian National University, Canberra, ACT 0200, Australia
    Cell Host Microbe 13:227-37. 2013
    ..The mutant parasites also show some impairment of Na(+) regulation. Taken together, our results are consistent with PfATP4 being a Na(+) efflux ATPase and a target of the spiroindolones...
  8. pmc Mitotic evolution of Plasmodium falciparum shows a stable core genome but recombination in antigen families
    Selina E R Bopp
    Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California, USA
    PLoS Genet 9:e1003293. 2013
    ..falciparum. These results will help improve our understanding of how P. falciparum evolves to evade control efforts within both the individual hosts and large populations...
  9. pmc Nuclear repositioning precedes promoter accessibility and is linked to the switching frequency of a Plasmodium falciparum invasion gene
    Bradley I Coleman
    Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA
    Cell Host Microbe 12:739-50. 2012
    ..Thus, nuclear repositioning is associated with increased P. falciparum switching frequency, while promoter accessibility is tightly linked to clonally active PfRh4 promoters...
  10. pmc Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design
    Michael B Harbut
    Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA
    Proc Natl Acad Sci U S A 109:21486-91. 2012
    ..Collectively, these data suggest ER quality control as a vulnerability of protozoan parasites, and that SPP inhibition may represent a suitable transmission blocking antimalarial strategy and potential pan-protozoan drug target...
  11. pmc Synthesis and biological evaluation of epidithio-, epitetrathio-, and bis-(methylthio)diketopiperazines: synthetic methodology, enantioselective total synthesis of epicoccin G, 8,8'-epi-ent-rostratin B, gliotoxin, gliotoxin G, emethallicin E, and haematoc
    K C Nicolaou
    Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    J Am Chem Soc 134:17320-32. 2012
    ..e., 46, 2,2'-epi-46, and 61) and several low-micromolar anti- Plasmodium falciparum lead compounds (i.e., 46, 2,2'-epi-46, 58, 61, and 1)...
  12. pmc Selective and specific inhibition of the plasmodium falciparum lysyl-tRNA synthetase by the fungal secondary metabolite cladosporin
    Dominic Hoepfner
    Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, Basel, Switzerland
    Cell Host Microbe 11:654-63. 2012
    ..Our data indicate that lysyl-tRNA synthetase is an attractive, druggable, antimalarial target that can be selectively inhibited...
  13. pmc Imidazolopiperazines: lead optimization of the second-generation antimalarial agents
    Advait Nagle
    Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA
    J Med Chem 55:4244-73. 2012
    ..They exhibit moderate oral exposure in rat pharmacokinetic studies to achieve sufficient multiples of the oral exposure at the efficacious dose in toxicology studies...
  14. pmc The activities of current antimalarial drugs on the life cycle stages of Plasmodium: a comparative study with human and rodent parasites
    Michael Delves
    Department of Life Sciences, Imperial College London, London, UK
    PLoS Med 9:e1001169. 2012
    ..These new medicines are needed both to meet the challenge of malaria eradication and to circumvent resistance...
  15. pmc Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery
    Stephan Meister
    Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA
    Science 334:1372-7. 2011
    ..The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms...
  16. pmc Identification of pathogen genomic variants through an integrated pipeline
    Micah J Manary
    Department of Pediatrics, University of California, San Diego, School of Medicine, 9500 Gilman Drive 0741, La Jolla, California 92093, USA
    BMC Bioinformatics 15:63. 2014
    ..We present methods for the analysis of small eukaryotic genomes, including a streamlined system (called Platypus) for finding single nucleotide and copy number variants as well as recombination events...

Research Grants30

  1. T cell Inhibitory receptor blockade in chronic blood-stage malaria
    John T Harty; Fiscal Year: 2013
    ..chabaudi chabaudi blood-stage infection. Aim 4. Determine if and how inhibitory receptor blockade during chronic blood-stage infection impacts cross- species and cross-stage-specific protective immunity to reinfection. ..
  2. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  3. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  4. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  5. Novel Broad-spectrum Antimalarials
    Victor Melendez; Fiscal Year: 2013
    ....
  6. FOSMIDOMYCIN RESISTANCE IN PLASMODIUM FALCIPARUM
    AUDREY RAGAN ODOM; Fiscal Year: 2013
    ..falciparum genome, and identify new targets for much-needed antimalarial drug development. ..
  7. Deciphering apicoplast function during blood stage Plasmodium infection
    Ellen Yeh; Fiscal Year: 2013
    ..The proposed research and career development activities will be critical in the preparation for an academic career and provide ample opportunities for a future in independent research. ..
  8. Mitochondrial Functions in Malaria Parasites
    Akhil B Vaidya; Fiscal Year: 2013
    ..These studies have the potential to be highly valuable in developing strategies for chemotherapeutic intervention affecting validated targets of malaria parasites. ..
  9. Small molecule protein-glycan inhib. as malaria transmission-blocking therapuetic
    RHOEL DAVID RAMOS DINGLASAN; Fiscal Year: 2013
    ....
  10. Lead optimization of DHODH inhibitors for malaria
    Margaret A Phillips; Fiscal Year: 2013
    ..Successful completion of these aims will identify additional DHODH inhibitors with the potential to be advanced for the treatment of malaria. ..
  11. Drugs targeting erythrocytic and exoerythrocytic stages of malaria
    Roman Manetsch; Fiscal Year: 2013
    ..The three chemotypes possess in vivo liver stage activity, in vivo blood stage activity, gametocytocidal activity, and/or activity in the mosquitoes. ..
  12. Southeast Regional Centers of Excellence for Biodefense &Emerging Infectious Di
    Philip Frederick Sparling; Fiscal Year: 2013
    ..SERCEB brings new investigators to the biodefense effort through a combination of educational programs, support of innovative new projects, and the synergistic interactions among its world-class investigators. ..