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  3. A non-reactive natural product precursor of the duocarmycin family has potent and selective antimalarial activity

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

  • Cell Chem Biol. 2022 May 19;29(5):840-853.e6. doi: 10.1016/j.chembiol.2021.10.005.
Arne Alder 1,  Nicole S Struck 2,  Min Xu 3,  Jarrod W Johnson 3,  Wenliang Wang 3,  Daniel Pallant 3,  Michael A Cook 3,  Janis Rambow 1,  Sarah Lemcke 1,  Tim W Gilberger 4,  Gerard D Wright 5
Affiliations

Affiliations

  • 1 Centre for Structural Systems Biology, 22607 Hamburg, Germany; Bernhard Nocht Institute for Tropical Medicine, Department of Cellular Parasitology, 20359 Hamburg, Germany; University of Hamburg, Department of Biology, 20146 Hamburg, Germany.
  • 2 Bernhard Nocht Institute for Tropical Medicine, Department of Cellular Parasitology, 20359 Hamburg, Germany; M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada; German Centre for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany.
  • 3 M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
  • 4 Centre for Structural Systems Biology, 22607 Hamburg, Germany; Bernhard Nocht Institute for Tropical Medicine, Department of Cellular Parasitology, 20359 Hamburg, Germany; University of Hamburg, Department of Biology, 20146 Hamburg, Germany. Electronic address: [email protected].
  • 5 M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada. Electronic address: [email protected].
PMID: 34710358 DOI: 10.1016/j.chembiol.2021.10.005
Abstract

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.

Keywords

Malaria; Plasmodium falciparum; antimalarial drugs; natural product screening.

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