Key result
The benzoxaborole AN13762 targets TgCPSF3 in apicomplexan parasites and demonstrates oral efficacy in a cryptosporidiosis mouse model.
Why the study?
The benzoxaborole AN13762 was identified as a preclinical candidate against the human malaria parasite, but its molecular target remained uncertain.
AN13762 is a promising preclinical candidate targeting CPSF3 with oral efficacy against cryptosporidiosis.
Identifies AN13762 target in malaria models; leaves open translation to human therapy.
Boron-containing compounds represent a promising class of molecules with proven efficacy against a wide range of pathogens, including apicomplexan parasites. Following lead optimization, the benzoxaborole AN13762 was identified as a preclinical candidate against the human malaria parasite, yet the molecular target remained uncertain. Here, we uncovered the parasiticidal mechanisms of AN13762, by combining forward genetics with transcriptome sequencing and computational mutation discovery and using Toxoplasma gondii as a relevant model for Apicomplexa. AN13762 was shown to target TgCPSF3, the catalytic subunit of the pre-mRNA cleavage and polyadenylation complex, as the anti-pan-apicomplexan benzoxaborole compound, AN3661. However, unique mutations within the TgCPSF3 catalytic site conferring resistance to AN13762 do not confer cross-protection against AN3661, suggesting a divergent resistance mechanism. Finally, in agreement with the high sequence conservation of CPSF3 between Toxoplasma and Cryptosporidium, AN13762 shows oral efficacy in cryptosporidiosis mouse model, a disease for which new drug development is of high priority.
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Bellini et al. (2020) studied Apicomplexan parasite infection (Malaria, Toxoplasmosis, Cryptosporidiosis). AN13762 was evaluated on Target identification and in vivo efficacy. The benzoxaborole AN13762 targets TgCPSF3 in apicomplexan parasites and demonstrates oral efficacy in a cryptosporidiosis mouse model.
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