![]() Fexinidazole, the first all-orally administered drug targeting trypanosomatids, was recently approved by the US Food and Drug Administration (FDA). Phenotypic screening approaches have also identified inhibitors. cruzi (the causative parasite of Chagas disease), and Leishmania major (parasite causing leishmaniasis) 7, 8, 9. Structure-guided docking studies have identified Pteridine Reductase 1 (PTR1) inhibitors of three highly related trypanosomatids, T. These inhibitors are predicted to bind the ATP-binding pocket of the TbREL1 protein 6. brucei RNA-editing ligase 1 (REL1) inhibitors have also been identified by virtual screening of a compound library. brucei N-myristoyltransferase inhibitors 5. Target-based high-throughput screening (HTS) of a compound library identified T. In recent years, several attempts have been made to develop new lines of therapeutics (reviewed in refs. New therapeutics are thus urgently needed. There are no good treatment options for nagana. However, melarsoprol is highly toxic and eflornithine is difficult to administer and costly, and many, including melarsoprol, suramin, and pentamidine have problems with drug resistance 2, 3. 2, 3) melarsoprol, eflornithine, and a combination of eflornithine and nifurtimox are used for late meningoencephalitic stage infection in which parasites invade the central nervous system (CNS) after crossing the blood–brain barrier 2, 3. Four drugs and combination therapy have been used for the treatment of HAT: suramin and pentamidine target the early hemolymphatic stage of infection (reviewed in refs. African trypanosomiasis is one of 20 “neglected tropical diseases” designated by the World Health Organization (WHO). Transmission of the parasite occurs through biting by infected tsetse flies ( Glossina spp.) 1. This parasite also causes nagana, a form of trypanosomiasis found in cattle and other livestock. T rypanosoma brucei is a protozoan parasite that causes African trypanosomiasis in humans (Human African Trypanosomiasis, HAT) in sub-Saharan Africa. Our data suggest a path toward developing and testing highly specific inhibitors for the treatment of African trypanosomiasis. Residue Serine 105 determines specific binding and inhibition of TbRPA1 but not T. Site-directed mutagenesis confirms that the DNA-Binding Domain A (DBD-A) in TbRPA1 contains a JC-229 binding pocket. cruzi and Leishmania RPA1, JC-229 only impacts the ssDNA-binding activity of TbRPA1. Indeed, despite the high sequence identity with T. In-vitro ssDNA-binding assays demonstrate that JC-229 inhibits the activity of TbRPA1, but not the human ortholog. JC-229 treatment mimics the effects of TbRPA1 depletion, including DNA replication inhibition and DNA damage accumulation. brucei cells, while mildly toxic to human cells. Using structural modeling, we discover an inhibitor, JC-229, that targets RPA1 in Trypanosoma brucei, the causative parasite of African trypanosomiasis. RPA protects the exposed single-stranded DNA (ssDNA) during DNA replication and repair. Replication Protein A (RPA) is a broadly conserved complex comprised of the RPA1, 2 and 3 subunits. ![]()
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