Author: Daniela Begolo, Isabel M. Vincent,Federica Giordani,Ina Pöhner,Michael J. Witty,Timothy G. Rowan,Zakaria Bengaly,Kirsten Gillingwater,Yvonne Freund,Rebecca C. Wade,Michael P. Barrett,Christine Clayton
Year: 2018
About this Publication:
Benzoxaborole-based compounds are very promising potential novel anti-trypanosomal therapies, with candidates already in human and animal clinical trials. We investigated the mechanism of action of several benzoxaboroles, including AN7973, an early candidate for veterinary trypanosomosis. Results chemically validate mRNA processing as a viable drug target in trypanosomes. Several other benzoxaboroles showed metabolomic and splicing effects that were similar to those of AN7973, identifying splicing inhibition as a common mode of action and suggesting that it might be linked to subsequent changes in methylated metabolites. Granule formation, splicing inhibition and resistance after CPSF3 expression did not, however, always correlate and prolonged selection of trypanosomes in AN7973 resulted in only 1.5-fold resistance. It is therefore possible that the modes of action of oxaboroles that target trypanosome mRNA processing might extend beyond CPSF3 inhibition
Grant: Tryps2
Subject Areas: Research and Development
Diseases: Trypanosomosis
URL https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1007315
Keywords:
AAT, African African Trypanosomosis, Benzoxaborole, Cattle, Protozoan, R&D, RNA, Resistance, Trypanosomiasis, Tryps, potential candidate
Countries:
Benin, Botswana, Burkina Faso, Burundi, Cape Verde, Comoros, Cote D'Ivoire, Djibouti, Eritrea, Ethiopia, Gambia, Ghana, Guinea, Guinea-Bissau, Kenya, Lesotho, Liberia, Madagascar, Malawi, Mali, Mauritania, Mauritius, Mayotte, Mozambique, Namibia, Niger, Nigeria, Reunion, Rwanda, Saint Helena, Senegal, Seychelles, Sierra Leone, Somalia, South Africa, Swaziland, Tanzania, United Republic Of, Togo, Uganda, Zambia, Zimbabwe