Minor groove binders as antitrypanosomal agents for animal African trypanosomiasis

Mon9  Apr05:15pm(15 mins)
Where:
Stream 1 - Edward Llwyd 0.26 Biology Main

Authors

F Giordani6; K Gillingwater4; A I Khalaf5; F J Scott5; C J Suckling5; L J Morrison3; H P de Koning2; R Peter1; M Witty1; M P Barrett6
1 GALVmed, UK;  2 Institute of Infection, Immunity and Inflammation, University of Glasgow, UK;  3 Roslin Institute, UK;  4 Swiss Tropical and Public Health Institute, Switzerland;  5 University of Strathclyde, UK;  6 Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, UK

Discussion

Current treatments for animal African trypanosomiasis (AAT) suffer from many limitations including limited efficacy, narrow safety range and, of particular concern, a rise in drug resistance. No new compounds have been introduced in over 50 years, limiting the control options for this livestock disease, which remains a major scourge for African farmers. With the establishment of dedicated public-private partnerships and expanded international interest, the development of drugs for AAT is back on the agenda. We are developing a novel class of anti-infective compounds called S-MGBs (Strathclyde Minor Groove Binders), which have great promise as veterinary trypanocides. The compounds are cidal against all of the three main Trypanosoma species causing AAT, an important property as in the field mixed infections with T. congolense, T. vivax and T. b. brucei are common and species diagnosis is seldom carried out before treatment. Lead candidates are curative in trypanosome-infected mice and, notably, do not show any cross-resistance to the diamidine and phenanthridine drugs currently licensed for AAT. Investigations into S-MGBs mode of action revealed perturbations to the integrity and function of nucleic acids, including an increase in cellular nucleotide content and partial inhibition of DNA synthesis upon treatment. Accumulation of parasites with multiple kinetoplasts, nuclei and flagella was also observed, indicative of a cytokinesis block. Although the S-MGBs concentrate within the nucleus and kinetoplast, they also localise to other cellular compartments which may offer further clues into their mode of action.

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