A non-reactive natural product precursor of the duocarmycin family has potent and selective antimalarial activity Journal Articles uri icon

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  • We identify a selective nanomolar inhibitor of blood-stage malarial proliferation from a screen of microbial natural product extracts. The responsible compound, PDE-I2, is a precursor of the anticancer duocarmycin family that preserves the class's sequence-specific DNA binding but lacks its signature DNA alkylating cyclopropyl warhead. While less active than duocarmycin, PDE-I2 retains comparable antimalarial potency to chloroquine. Importantly, PDE-I2 is >1,000-fold less toxic to human cell lines than duocarmycin, with mitigated impacts on eukaryotic chromosome stability. PDE-I2 treatment induces severe defects in parasite nuclear segregation leading to impaired daughter cell formation during schizogony. Time-of-addition studies implicate parasite DNA metabolism as the target of PDE-I2, with defects observed in DNA replication and chromosome integrity. We find the effect of duocarmycin and PDE-I2 on parasites is phenotypically indistinguishable, indicating that the DNA binding specificity of duocarmycins is sufficient and the genotoxic cyclopropyl warhead is dispensable for the parasite-specific selectivity of this compound class.


  • Alder, Arne
  • Struck, Nicole S
  • Xu, Min
  • Johnson, Jarrod W
  • Wang, Wenliang
  • Pallant, Daniel
  • Cook, Michael A
  • Rambow, Janis
  • Lemcke, Sarah
  • Gilberger, Tim W
  • Wright, Gerard

publication date

  • May 2022