Target Identification of an Antimalarial Oxaborole Identifies AN13762 as an Alternative Chemotype for Targeting CPSF3 in Apicomplexan Parasites

iScience

Alexandre Bougdour¹  Tiffany Pezier²  Fabrice Laurent²  Mohamed-Ali Hakimi³  Christopher Swale³  Valeria Bellini³  Marie-Pierre Brenier-Pinchart³  Sonia Georgeault⁴ 

[1] Corresponding author;INRAE, Université François Rabelais de Tours, Centre Val de Loire, UMR1282 ISP, Laboratoire Apicomplexes et Immunité Mucosale, 37380 Nouzilly, France;Institute for Advanced Biosciences (IAB), Host-Pathogen Interactions and Immunity to Infection, INSERM U1209, CNRS UMR 5309, University Grenoble Alpes, 38000 Grenoble, France;Plateforme des Microscopies, Université et CHRU de Tours, 37000 Tours, France;

关键词: Molecular Biology;    Molecular Medicine;    Microbiology;    Microbiology Parasite;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: 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.

【 授权许可】

Unknown