Supplementary Materials

Supplementary Material for:

A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria

Margaret A. Phillips,* Julie Lotharius, Kennan Marsh, John White, Anthony Dayan, Karen L. White, Jacqueline W. Njoroge, Farah El Mazouni, Yanbin Lao, Sreekanth Kokkonda, Diana R. Tomchick, Xiaoyi Deng, Trevor Laird, Sangeeta N. Bhatia, Sandra March, Caroline L. Ng, David A. Fidock, Sergio Wittlin, Maria Lafuente-Monasterio, Francisco Javier Gamo Benito, Laura Maria Sanz Alonso, Maria Santos Martinez, Maria Belen Jimenez-Diaz, Santiago Ferrer Bazaga, I�igo Angulo-Barturen, John N. Haselden, James Louttit, Yi Cui, Arun Sridhar, Anna-Marie Zeeman, Clemens Kocken, Robert Sauerwein, Koen Dechering, Vicky M. Avery, Sandra Duffy, Michael Delves, Robert Sinden, Andrea Ruecker, Kristina S. Wickham, Rosemary Rochford, Janet Gahagen, Lalitha Iyer, Ed Riccio, Jon Mirsalis, Ian Bathhurst, Thomas Rueckle, Xavier Ding, Brice Campo, Didier Leroy, M. John Rogers, Pradipsinh K. Rathod, Jeremy N. Burrows, Susan A. Charman*

*Corresponding author. E-mail: margaret.phillips{at}utsouthwestern.edu (M.A.P.); susan.charman{at}monash.edu

Published 15 July 2015, Sci. Transl. Med. 7, 296ra111 (2015)
DOI: 10.1126/scitranslmed.aaa6645

This PDF file includes:

  • Synthesis
  • Materials and Methods
  • Fig. S1. (Fo-Fc) map for DSM265:PfDHODH binding site.
  • Fig. S2. DHODH sequence alignment.
  • Fig. S3. In vitro parasite killing curves.
  • Fig. S4. Activity of DSM265 against P. cynomolgi large (liver schizonts) and small (hypnozoite) forms.
  • Fig. S5. The effect of DSM265 treatment on P. falciparum Pf3D70087/N9 in vivo.
  • Fig. S6A. Proposed biotransformation pathways of DSM265 in plasma of mice, rabbits, monkeys, and dogs.
  • Fig. S6B. Plasma concentrations of DSM265 and DSM450 (hydroxy metabolite).
  • Fig. S7. Simulated human plasma profiles using a PBPK model (GastroPlus).
  • Fig. S8. Effect on ECG in the rabbit cardiac ventricular wedge assay.
  • Fig. S9. Evaluation of the effects of DSM265 on G6PD-deficient human RBCs engrafted into a NOD-SCID mouse.
  • Table S1. PfDHODH-DSM265 x-ray diffraction data and refinement statistics.
  • Table S2. In vitro antimalarial activity of DSM265.
  • Table S3A. Blood pharmacokinetic data for DSM265 in SCID mice.
  • Table S3B. SCID mouse in vivo antimalarial activity.
  • Table S3C. SCID mouse parasitemia.
  • Table S3D. SCID mouse pharmacokinetic individual time point data.
  • Table S4A. Selection for DSM265-resistant parasites in P. falciparum Dd2: Rathod laboratory.
  • Table S4B. Selection for atovaquone-resistant parasites in P. falciparum Dd2: Rathod laboratory.
  • Table S4C. Selection for DSM265-resistant parasites in P. falciparum Dd2: Fidock laboratory.
  • Table S4D. Selection for atovaquone-resistant parasites in P. falciparum Dd2: Fidock laboratory.
  • Table S4E. Selection for DSM265-resistant parasites in P. falciparum K1: Fidock laboratory.
  • Table S4F. Selection for DSM265 and atovaquone P. falciparum HB3: Rathod laboratory.
  • Table S5. Summary of DSM265-resistant clones: Analysis of parasites in whole-cell assays.
  • Table S6. Kinetic analysis of PfDHODH mutants.
  • Table S7. Drug combination analysis.
  • Table S8A. Stability data for DSM265 free base and tosylate salt.
  • Table S8B. Solubility data for DSM265 free base.
  • Table S9. In vitro ADME data for DSM265.
  • Table S10. In vivo metabolite identification.
  • Table S11. Relative plasma exposures of DSM265 metabolites in mice, rabbits, monkeys, and dogs.
  • Table S12. DSM265 plasma pharmacokinetics after a single intravenous dose in mice, rats, dogs, and monkey.
  • Table S13. DSM265 plasma pharmacokinetics after a single oral dose of DSM265 in mice, rats, dogs, and monkeys.
  • Table S14. Effect of salt form, formulation, and food on the DSM265 plasma pharmacokinetics after oral dosing in beagle dogs.
  • Table S15. Safety pharmacology.
  • Table S16. Exploratory toxicology studies (non-GLP) in rodents and dogs.
  • Table S17A. Toxicokinetic parameters on days 1 and 7 in a mouse 7-day toxicology study.
  • Table S17B. Individual mouse plasma concentrations 7-day toxicology study 25 mg/kg.
  • Table S17C. Individual mouse plasma concentrations 7-day toxicology study 75 mg/kg.
  • Table S17D. Individual mouse plasma concentrations 7-day toxicology study 200 mg/kg.
  • Table S18A. Toxicokinetic data from a 10-day toxicology study in male beagle dogs.
  • Table S18B. Toxicokinetic parameters day 1 of toxicology study in male beagle dogs.
  • Table. S19. Primary data supporting Fig. 2.
  • Table. S20. Primary data supporting Fig. 3 (A and B).
  • Table. S21. Primary data supporting Fig. 5.
  • References (3866)

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