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

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Giordani, Federica and Khalaf, Abedawn I. and Gillingwater, Kirsten and Munday, Jane C. and De Koning, Harry P. and Suckling, Colin J. and Barrett, Michael P. and Scott, Fraser 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. ISSN 0022-2623 (https://doi.org/10.1021/acs.jmedchem.8b01847)

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Abstract

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.

ORCID iDs

Giordani, Federica, Khalaf, Abedawn I. ORCID logoORCID: https://orcid.org/0000-0001-9162-7527, Gillingwater, Kirsten, Munday, Jane C., De Koning, Harry P., Suckling, Colin J., Barrett, Michael P. and Scott, Fraser J. ORCID logoORCID: https://orcid.org/0000-0003-0229-3698;
CORE (COnnecting REpositories)