Novel Minor Groove Binders cure animal African trypanosomiasis in an in vivo mouse model

Federica Giordani, Abedawn I. Khalaf, Kirsten Gillingwater, Jane C. Munday, Harry P. De Koning, Colin J. Suckling, Michael Barrett, Fraser Scott

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)3021-3035
Number of pages15
JournalJournal of Medicinal Chemistry
Volume62
Issue number6
Early online date14 Feb 2019
DOIs
Publication statusPublished - 28 Mar 2019

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