Novel minor groove binders cure animal african trypanosomiasis in an in vivo mouse model

GIordani, F. and Khalaf, A. I. and Gillingwater, K. and Munday, J. C. and De Koning, H. P. and Suckling, C. J. and Barrett, M. P. and Scott, F. J.. (2019) Novel minor groove binders cure animal african trypanosomiasis in an in vivo mouse model. Journal of medicinal chemistry, 62 (6). pp. 3021-3035.

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Official URL: https://edoc.unibas.ch/70113/

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Animal African trypanosomiasis (AAT) is a significant socioeconomic burden for sub-Saharan Africa because of its huge impact on livestock health. Existing therapies including those based on minor groove binders (MGBs), such as the diamidines, which have been used for decades, have now lost efficacy in some places because of the emergence of resistant parasites. Consequently, the need for new chemotherapies is urgent. Here, we describe a structurally distinct class of MGBs, Strathclyde MGBs (S-MGBs), which display excellent in vitro activities against the principal causative organisms of AAT: Trypanosoma congolense, and Trypanosoma vivax. We also show the cure of T. congolense-infected mice by a number of these compounds. In particular, we identify S-MGB-234, compound 7, as curative by using two applications of 50 mg/kg intraperitoneally. Crucially, we demonstrate that S-MGBs do not show cross-resistance with the current diamidine drugs and are not internalized via the transporters used by diamidines. This study demonstrates that S-MGBs have significant potential as novel therapeutic agents for AAT.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Gillingwater, Kirsten
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:04 Apr 2019 12:00
Deposited On:04 Apr 2019 07:44

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