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

Aditi Mukherjee, Zakir Hossain, Esteban Erben, Shuai Ma, Jun Yong Choi () and Hee-Sook Kim ()
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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)
Shuai Ma: The Graduate Center of the City University of New York
Jun Yong Choi: Queens College
Hee-Sook Kim: Rutgers Biomedical Health Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39839-x

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