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Bumped Kinase Inhibitors Inhibit both Toxoplasma gondii MAPKL1 and CDPK1.

Jemma A Montgomery1, P Holland Alday1,2, Ryan Choi3

  • 1Division of Infectious Diseases, Portland VA Medical Center, Portland, Oregon 97239, United States.

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|May 23, 2025
PubMed
Summary
This summary is machine-generated.

Bumped kinase inhibitors (BKIs) target calcium-dependent protein kinase 1 (TgCDPK1) and mitogen-activated protein kinase-like 1 (TgMAPKL1) in Toxoplasma gondii. Dual targeting suggests a high genetic barrier to drug resistance, aiding therapeutic development.

Keywords:
antiparasitic drugsbumped kinase inhibitordrug mechanismkinasetherapeuticstoxoplasmosis

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Area of Science:

  • Parasitology
  • Drug Discovery
  • Molecular Biology

Background:

  • Bumped kinase inhibitors (BKIs) are optimized to target calcium-dependent protein kinase 1 (TgCDPK1) in Toxoplasma gondii and Cryptosporidium.
  • BKI-1748 is a lead compound for toxoplasmosis, but its precise mechanism of action requires further investigation.
  • Previous studies suggested potential off-target effects of BKIs beyond TgCDPK1.

Purpose of the Study:

  • To elucidate the mechanism of action of BKI-1748.
  • To identify additional targets of BKIs in Toxoplasma gondii.
  • To assess the genetic basis for resistance to BKIs.

Main Methods:

  • Forward genetic screen using chemical mutagenesis to generate BKI-1748 resistant clones.
  • Whole genome sequencing to identify mutations in resistant clones.
  • Site-directed mutagenesis to introduce specific mutations (TgMAPKL1 Leu162Gln, TgCDPK1 Gly128Met) into wild-type strains.

Main Results:

  • Resistant clones exhibited single nucleotide changes in the ATP binding site of TgMAPKL1.
  • Specific mutations in TgMAPKL1 and TgCDPK1 conferred 2-to-6-fold and similar resistance, respectively.
  • Combined mutations in TgMAPKL1 and TgCDPK1 resulted in a significant increase in resistance (up to 157-fold).

Conclusions:

  • TgMAPKL1, in addition to TgCDPK1, is identified as a target of BKIs.
  • Understanding dual targeting enhances knowledge of BKI mechanism of action for therapeutic development.
  • A high genetic barrier to drug resistance is suggested for this class of compounds.