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⇱ Chemical genetics of Plasmodium falciparum | Nature

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Abstract

Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire library—many of which showed potent in vitro activity against drug-resistant P. falciparum strains—and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery.

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Figure 1: Chemical structure network graph and antimalarial potencies of the 1,300 primary screen hits.
Figure 2: Reduced representation of the network map showing synergistic activities with clinically relevant antimalarials.
Figure 3: Reduced representation of the network map showing the interaction of the cross-validated hits with potential biological targets.
Figure 4: Phylochemogenetic profiling.

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References

  1. Wongsrichanalai, C. & Meshnick, S. R. Declining artesunate-mefloquine efficacy against falciparum malaria on the Cambodia-Thailand border. Emerg. Infect. Dis. 14, 716–719 (2008)

    Article  Google Scholar 

  2. Dondorp, A. M. et al. Artemisinin resistance in Plasmodium falciparum malaria. N. Engl. J. Med. 361, 455–467 (2009)

    Article  CAS  Google Scholar 

  3. Ridley, R. G. Medical need, scientific opportunity and the drive for antimalarial drugs. Nature 415, 686–693 (2002)

    Article  CAS  Google Scholar 

  4. Kissinger, J. C. et al. The Plasmodium genome database. Nature 419, 490–492 (2002)

    Article  ADS  CAS  Google Scholar 

  5. Baniecki, M. L., Wirth, D. F. & Clardy, J. High-throughput Plasmodium falciparum growth assay for malaria drug discovery. Antimicrob. Agents Chemother. 51, 716–723 (2007)

    Article  CAS  Google Scholar 

  6. Plouffe, D. et al. In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen. Proc. Natl Acad. Sci. USA 105, 9059–9064 (2008)

    Article  ADS  CAS  Google Scholar 

  7. Weisman, J. L. et al. Searching for new antimalarial therapeutics amongst known drugs. Chem. Biol. Drug Des. 67, 409–416 (2006)

    Article  CAS  Google Scholar 

  8. Wells, T. N., Alonso, P. L. & Gutteridge, W. E. New medicines to improve control and contribute to the eradication of malaria. Nature Rev. Drug Discov. 8, 879–891 (2009)

    Article  CAS  Google Scholar 

  9. Munos, B. Can open-source R&D reinvigorate drug research? Nature Rev. Drug Discov. 5, 723–729 (2006)

    Article  CAS  Google Scholar 

  10. Shelat, A. A. & Guy, R. K. Scaffold composition and biological relevance of screening libraries. Nature Chem. Biol. 3, 442–446 (2007)

    Article  ADS  CAS  Google Scholar 

  11. Shelat, A. A. & Guy, R. K. The interdependence between screening methods and screening libraries. Curr. Opin. Chem. Biol. 11, 244–251 (2007)

    Article  CAS  Google Scholar 

  12. Smilkstein, M. et al. Simple and inexpensive fluorescence-based technique for high-throughput antimalarial drug screening. Antimicrob. Agents Chemother. 48, 1803–1806 (2004)

    Article  CAS  Google Scholar 

  13. Cibulskis, R. E. et al. Estimating trends in the burden of malaria at country level. Am. J. Trop. Med. Hyg. 77, (suppl. 6)133–135 (2007)

    Article  Google Scholar 

  14. Gujjar, R. et al. Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice. J. Med. Chem. 52, 1864–1872 (2009)

    Article  CAS  Google Scholar 

  15. Patel, V. et al. Identification and characterization of small molecule inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. J. Biol. Chem. 283, 35078–35085 (2008)

    Article  CAS  Google Scholar 

  16. Weissbuch, I. & Leiserowitz, L. Interplay between malaria, crystalline hemozoin formation, and antimalarial drug action and design. Chem. Rev. 108, 4899–4914 (2008)

    Article  CAS  Google Scholar 

  17. Pisciotta, J. M. et al. The role of neutral lipid nanospheres in Plasmodium falciparum haem crystallization. Biochem. J. 402, 197–204 (2007)

    Article  CAS  Google Scholar 

  18. Sijwali, P. S. & Rosenthal, P. J. Gene disruption confirms a critical role for the cysteine protease falcipain-2 in hemoglobin hydrolysis by Plasmodium falciparum . Proc. Natl Acad. Sci. USA 101, 4384–4389 (2004)

    Article  ADS  CAS  Google Scholar 

  19. Sijwali, P. S., Koo, J., Singh, N. & Rosenthal, P. J. Gene disruptions demonstrate independent roles for the four falcipain cysteine proteases of Plasmodium falciparum . Mol. Biochem. Parasitol. 150, 96–106 (2006)

    Article  CAS  Google Scholar 

  20. Crowther, G. J. et al. Buffer optimization of thermal melt assays of Plasmodium proteins for detection of small-molecule ligands. J. Biomol. Screen. 14, 700–707 (2009)

    Article  CAS  Google Scholar 

  21. Witola, W. H. et al. Disruption of the Plasmodium falciparum PfPMT gene results in a complete loss of phosphatidylcholine biosynthesis via the serine-decarboxylase-phosphoethanolamine-methyltransferase pathway and severe growth and survival defects. J. Biol. Chem. 283, 27636–27643 (2008)

    Article  CAS  Google Scholar 

  22. Krnajski, Z. et al. Thioredoxin reductase is essential for the survival of Plasmodium falciparum erythrocytic stages. J. Biol. Chem. 277, 25970–25975 (2002)

    Article  CAS  Google Scholar 

  23. McFadden, G. I. & Roos, D. S. Apicomplexan plastids as drug targets. Trends Microbiol. 7, 328–333 (1999)

    Article  CAS  Google Scholar 

  24. Reynolds, M. G. & Roos, D. S. A biochemical and genetic model for parasite resistance to antifolates. Toxoplasma gondii provides insights into pyrimethamine and cycloguanil resistance in Plasmodium falciparum . J. Biol. Chem. 273, 3461–3469 (1998)

    Article  CAS  Google Scholar 

  25. Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 46, 3–26 (2001)

    Article  CAS  Google Scholar 

  26. Shenai, B. R. et al. Structure-activity relationships for inhibition of cysteine protease activity and development of Plasmodium falciparum by peptidyl vinyl sulfones. Antimicrob. Agents Chemother. 47, 154–160 (2003)

    Article  CAS  Google Scholar 

  27. Ritz, C. & Streibig, J. C. Bioassay analysis using R. J. Stat. Softw. 12, 22 (2005)

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the American Lebanese Syrian Associated Charities (ALSAC) and St Jude Children’s Research Hospital (SJCRH, R.K.G.), the Medicines for Malaria Venture (W.C.V.V. and V.M.A.), National Institute of Allergy and Infectious Diseases (AI772682 (P.H.D.), AI075517 (R.K.G.), AI067921 (W.C.V.V.) and AI080625 (W.C.V.V.), AI28724 (D.S.R.), AI53862 (J.L.D.), AI35707 (P.J.R.), AI053680 (M.A.P. and P.K.R.), AI075594 (M.A.P., P.K.R. and I.B.), AI082617 (P.K.R.) and AI045774 (D.J.S.)), the National Cancer Institute (CA78039 (J.S.L.)), the Welch Foundation (I-1257 (M.A.P.)), the Doris Duke Charitable Foundation (P.J.R.), and the Ellison Medical Foundation (D.S.R.). We acknowledge A. B. Vaidya for providing the parasite strain D10_yDHOD. We acknowledge M. Sigal for assistance in the early leads project coordination, the SJCRH High Throughput Screening Center, particularly J. Cui; the SJCRH Lead Discovery Informatics Center, and the SJCRH High Throughput Analytical Chemistry Center, particularly C. Nelson and A. Lemoff; at UW, F. Buckner, W. Hol and A. Napuli (AI067921, W. Hol); S. Wei and W. Hao in the UT Southwestern HTS Center; and the Australian Red Cross Blood Service for the provision of O+ erythrocytes to Griffith University.

Author information

Authors and Affiliations

  1. Department of Chemical Biology and Therapeutics, St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA,

    W. Armand Guiguemde, Anang A. Shelat, David Bouck, David C. Smithson, Michele Connelly, Julie Clark, Fangyi Zhu & R. Kiplin Guy

  2. Discovery Biology, Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane 4111, Australia

    Sandra Duffy & Vicky M. Avery

  3. Department of Medicine, University of Washington, Seattle, Washington 98195-7185, USA,

    Gregory J. Crowther & Wesley C. Van Voorhis

  4. Department of Biology and the Penn Genome Frontiers Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,

    Paul H. Davis & David S. Roos

  5. GlaxoSmithKline, Tres Cantos Medicines Development Campus, Diseases of Developing World, Tres Cantos 28760, Spain

    María B. Jiménez-Díaz, María S. Martinez, Iñigo Angulo-Barturen & Santiago Ferrer

  6. Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2542, USA,

    Emily B. Wilson & Joseph L. DeRisi

  7. W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA,

    Abhai K. Tripathi & David J. Sullivan

  8. Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94143, USA,

    Jiri Gut & Philip J. Rosenthal

  9. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA,

    Elizabeth R. Sharlow & John S. Lazo

  10. Medicines for Malaria Venture, Geneva 1215, Switzerland

    Ian Bathurst

  11. Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9041, USA,

    Farah El Mazouni & Margaret A. Phillips

  12. Department of Chemistry, University of Washington, Seattle, Washington 98195-7185, USA,

    Joseph W. Fowble & Pradipsinh K. Rathod

  13. Experimental Chemotherapy Lab, Portland VA Medical Center, Portland, Oregon 97239, USA ,

    Isaac Forquer & Michael K. Riscoe

  14. Department of Chemistry and Chemical Biology Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA,

    Paula L. McGinley & Steve Castro

Authors
  1. W. Armand Guiguemde
  2. Anang A. Shelat
  3. David Bouck
  4. Sandra Duffy
  5. Gregory J. Crowther
  6. Paul H. Davis
  7. David C. Smithson
  8. Michele Connelly
  9. Julie Clark
  10. Fangyi Zhu
  11. María B. Jiménez-Díaz
  12. María S. Martinez
  13. Emily B. Wilson
  14. Abhai K. Tripathi
  15. Jiri Gut
  16. Elizabeth R. Sharlow
  17. Ian Bathurst
  18. Farah El Mazouni
  19. Joseph W. Fowble
  20. Isaac Forquer
  21. Paula L. McGinley
  22. Steve Castro
  23. Iñigo Angulo-Barturen
  24. Santiago Ferrer
  25. Philip J. Rosenthal
  26. Joseph L. DeRisi
  27. David J. Sullivan
  28. John S. Lazo
  29. David S. Roos
  30. Michael K. Riscoe
  31. Margaret A. Phillips
  32. Pradipsinh K. Rathod
  33. Wesley C. Van Voorhis
  34. Vicky M. Avery
  35. R. Kiplin Guy

Contributions

W.A.G. and R.K.G. designed and coordinated the project. A.A.S. wrote the algorithms for the data analysis and generated the figures. Assays were conceived, performed and analysed by W.A.G. and D.B. (P. falciparum phenotypic screen), M.C. (human cell lines), D.C.S. (T. brucei), P.H.D. and D.S.R. (T. gondii), J.S.L. and E.R.S. (L. major), A.K.T. and D.J.S. (haemozoin inhibition), G.J.C. and W.C.V.V. (thermal melt experiments), M.A.P., P.K.R., F.E.M. and I.B. (PfDHOD), J.W.F. and P.K.R. (P. falciparum dihydrofolate reductase), J.G. and P.J.R. (PfFP-2), I.F. and M.K.R. (cytochrome bc1), J.C. (P. falciparum mutant drug sensitivity). E.B.W., S.D., J.L.D. and V.M.A. (independent antimalarial in vitro experiments), F.Z. (in vitro pharmacokinetics), M.B.J.D., M.S.M., I.A.-B. and S.F. (in vivo pharmacokinetics and efficacy), I.B. (coordination of technology development and network development), S.C. and P.L.M. (re-synthesis). W.A.G., A.A.S. and R.K.G. wrote the manuscript. All authors contributed to the design of the experiments and the preparation of the manuscript.

Corresponding author

Correspondence to R. Kiplin Guy.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information (download PDF )

This file contains Supplementary Information comprising: Compound Library Screened; Parasite and cell-based assay methods; Enzymatic and protein assays; Data processing and screening results; Multiple-lab cross-validation study; Chemical structure network graph; Additional mechanistic studies; Detailed analysis of three early lead compounds; Other high-value compounds; Data availability; Supplementary Tables S1-S8, Supplementary Figures S1-S5 with legends and References. The Supplementary Information file was replaced on 24 June 2010. (PDF 952 kb)

Supplementary Data (download XLS )

This file contains Structural information and Primary screening for 1536 compounds, Screening data from 228 compounds for the Bland-Altman analysis, Calculated medicinal chemistry properties, Cytotoxic activity, Screen sensitivity and Differential activity for 172 compounds, Raw data from the Hemozoin polymerization inhibition assay, summary of activity of 172 compounds in the thermal melt assays and Raw data and calculated Kd for thermal melt assay hits. (XLS 5090 kb)

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Guiguemde, W., Shelat, A., Bouck, D. et al. Chemical genetics of Plasmodium falciparum. Nature 465, 311–315 (2010). https://doi.org/10.1038/nature09099

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  • DOI: https://doi.org/10.1038/nature09099

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