Author: Smith A, Wall RJ, Patterson S, Rowan T, Vida ER, Stojanovski L, Huggett M, Hampton SE, Thomas MG, Lopez VC, Gillingwater K, Duke J, Napier G, Peter R, Vitouley HS, Harrison JR, Milne R, Jeacock L, Baker N, Davis SH, Simeons F, Riley J, Horn D, Brun R, Zuccotto F, Witty MJ, Wyllie S, Read KD, Gilbert IH.
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Grant: Tryps 3 African animal trypanosomiasis or nagana, caused principally by infection of the protozoan parasites Trypanosoma congolense and Trypanosoma vivax, is a major problem in cattle and other livestock species in sub-Saharan Africa. Current treatments are threatened by the emergence of drug resistance and there is an urgent need for new, effective drugs. Here, we report the repositioning of a compound series initially developed for the treatment of human African trypanosomiasis. A medicinal chemistry programme, focused on deriving more soluble analogues, led to development of a lead compound capable of curing cattle infected with both T. congolense and T. vivax when administered intravenously. Further optimisation has the potential to yield a single-dose intramuscular treatment for this disease. Comprehensive mode of action studies revealed that the molecular target of this promising compound and related analogues is the cyclin-dependent kinase CRK12.
Subject Areas: Research and Development