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Identification of a small-molecule inhibitor that selectively blocks DNA-binding by Trypanosoma brucei replication protein A1

Author

Listed:
  • Aditi Mukherjee

    (Rutgers Biomedical Health Sciences)

  • Zakir Hossain

    (Queens College)

  • Esteban Erben

    (Universidad Nacional de San Martín (UNSAM) – Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)
    Universidad Nacional de San Martín)

  • Shuai Ma

    (The Graduate Center of the City University of New York)

  • Jun Yong Choi

    (Queens College
    The Graduate Center of the City University of New York
    The Graduate Center of the City University of New York)

  • Hee-Sook Kim

    (Rutgers Biomedical Health Sciences
    Rutgers Biomedical Health Sciences)

Abstract

Replication Protein A (RPA) is a broadly conserved complex comprised of the RPA1, 2 and 3 subunits. RPA protects the exposed single-stranded DNA (ssDNA) during DNA replication and repair. Using structural modeling, we discover an inhibitor, JC-229, that targets RPA1 in Trypanosoma brucei, the causative parasite of African trypanosomiasis. The inhibitor is highly toxic to T. brucei cells, while mildly toxic to human cells. JC-229 treatment mimics the effects of TbRPA1 depletion, including DNA replication inhibition and DNA damage accumulation. In-vitro ssDNA-binding assays demonstrate that JC-229 inhibits the activity of TbRPA1, but not the human ortholog. Indeed, despite the high sequence identity with T. cruzi and Leishmania RPA1, JC-229 only impacts the ssDNA-binding activity of TbRPA1. Site-directed mutagenesis confirms that the DNA-Binding Domain A (DBD-A) in TbRPA1 contains a JC-229 binding pocket. Residue Serine 105 determines specific binding and inhibition of TbRPA1 but not T. cruzi and Leishmania RPA1. Our data suggest a path toward developing and testing highly specific inhibitors for the treatment of African trypanosomiasis.

Suggested Citation

  • Aditi Mukherjee & Zakir Hossain & Esteban Erben & Shuai Ma & Jun Yong Choi & Hee-Sook Kim, 2023. "Identification of a small-molecule inhibitor that selectively blocks DNA-binding by Trypanosoma brucei replication protein A1," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39839-x
    DOI: 10.1038/s41467-023-39839-x
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    References listed on IDEAS

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