Supplementary Materials

Supplementary Material for:

Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase

Tanya Paquet, Claire Le Manach, Diego González Cabrera, Yassir Younis, Philipp P. Henrich, Tara S. Abraham, Marcus C. S. Lee, Rajshekhar Basak, Sonja Ghidelli-Disse, María José Lafuente-Monasterio, Marcus Bantscheff, Andrea Ruecker, Andrew M. Blagborough, Sara E. Zakutansky, Anne-Marie Zeeman, Karen L. White, David M. Shackleford, Janne Mannila, Julia Morizzi, Christian Scheurer, Iñigo Angulo-Barturen, María Santos Martínez, Santiago Ferrer, Laura María Sanz, Francisco Javier Gamo, Janette Reader, Mariette Botha, Koen J. Dechering, Robert W. Sauerwein, Anchalee Tungtaeng, Pattaraporn Vanachayangkul, Chek Shik Lim, Jeremy Burrows, Michael J. Witty, Kennan C. Marsh, Christophe Bodenreider, Rosemary Rochford, Suresh M. Solapure, María Belén Jiménez-Díaz, Sergio Wittlin, Susan A. Charman, Cristina Donini, Brice Campo, Lyn-Marie Birkholtz, Kirsten K. Hanson, Gerard Drewes, Clemens H. M. Kocken, Michael J. Delves, Didier Leroy, David A. Fidock, David Waterson, Leslie J. Street, Kelly Chibale*

*Corresponding author. Email: kelly.chibale{at}uct.ac.za

Published 26 April 2017, Sci. Transl. Med. 9, eaad9735 (2017)
DOI: 10.1126/scitranslmed.aad9735

This PDF file includes:

  • Materials and Methods
  • Fig. S1. Activity of MMV390048 against NF54 asexual blood-stage parasites.
  • Fig. S2. Lack of growth of schizonts compared to rings after treatment with MMV390048.
  • Fig. S3. Onset and recrudescence experiments in the P. berghei mouse model using a single dose of 100 mg/kg compound.
  • Fig. S4. Whole-blood concentrations of MMV390048 after the first dose of treatment during the PfSCID mouse efficacy study.
  • Fig. S5. Observed and predicted blood PK profiles from PfSCID mouse efficacy study.
  • Fig. S6. Observed (symbols) and predicted (lines) parasite load in mouse based on the direct effect model and PfSCID mouse efficacy data.
  • Fig. S7. Prophylactic efficacy of MMV390048 in the P. cynomolgi liver-stage in vitro assay.
  • Fig. S8. MMV390048-resistant clones show a four- to fivefold shift in IC50 relative to the parental Dd2 strain.
  • Fig. S9. CNV analysis using the program BIC-Seq (23).
  • Fig. S10. IC50 of MMV390048 against ZFN-modified parasites with point mutations in PI4K or the parental Dd2 strain.
  • Fig. S11. Phylogenetic tree of the human (blue) and Plasmodium (red) lipid kinase family.
  • Fig. S12. Correlation between whole-cell NF54 activity and inhibition of PvPI4K across a selection of MMV390048 analogs.
  • Fig. S13. Pharmacokinetic profiles after intravenous and oral administration of MMV390048 to mice, rats, dogs, and monkeys.
  • Fig. S14. Allometric scaling of clearance from different species as a function of body weight.
  • Fig. S15. Assessment of hemolytic toxicity.
  • Table S1. Activity against a panel of resistant strains to determine potential for cross-resistance.
  • Table S2. In vitro parasite reduction data in support of Fig. 1B.
  • Table S3. Speed assay IC50 results in support of Fig. 1C.
  • Table S4. Efficacy data in the PfSCID mouse model in support of Fig. 1D.
  • Table S5. Summary of exposure data in the PfSCID mouse model after oral administration of MMV390048 once a day for four consecutive days.
  • Table S6. Estimated PK parameters from PfSCID mouse exposure with Ka fixed at 0.5/hour.
  • Table S7. Estimated PKPD parameters from PfSCID mouse parasitemia and exposure study.
  • Table S8. Estimated PKPD parameters from PfSCID mouse parasitemia and exposure study indicating highest net kill rate (red).
  • Table S9. Estimated EC50, EC90, and MIC based on modeling of highest net kill rate.
  • Table S10. Late-stage gametocyte viability measured by pLDH activity in support of Fig. 2B.
  • Table S11. Early- and late-stage gametocyte viability measured by luminescence in support of Fig. 2C.
  • Table S12. Early- and late-stage gametocyte clearance rates in support of Fig. 2D.
  • Table S13. Gametocytocidal activity.
  • Table S14. Inhibition of exflagellation in support of Fig. 2E.
  • Table S15. SMFA indirect mode results in support of Fig. 2F.
  • Table S16. SMFA direct mode results in support of Fig. 2F (inset).
  • Table S17. Parasitemias during the prophylactic P. cynomolgi–infected monkey study in support of Fig. 3A.
  • Table S18. Plasma concentrations of MMV390048 during the prophylactic P. cynomolgi–infected monkey study in support of Fig. 3B.
  • Table S19. Parasitemias during the radical cure P. cynomolgi–infected monkey study in support of Fig. 3C.
  • Table S20. Plasma concentrations of MMV390048 during the radical cure P. cynomolgi–infected monkey study in support of Fig. 3D.
  • Table S21. Number of triplicates at different inocula that became positive after MMV390048 treatment.
  • Table S22. Whole-genome sequence analysis of three cloned Dd2 parasite lines selected for resistance to compound MMV390048.
  • Table S23. Correlation between the degree of binding to PfPI4K, activity against PcPI4K, and antiparasitic activity of MMV390048 analogs.
  • Table S24. Plasma PK parameters after a single intravenous dose of MMV390048 in different species.
  • Table S25. Plasma PK parameters after a single oral dose of MMV390048 in different species.
  • Legends for tables S26 and S27
  • References (3853)

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Other Supplementary Material for this manuscript includes the following:

  • Table S26. Chemoproteomics data (provided in Excel).
  • Table S27. Proteomics data (provided in Excel).

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