Nature · 2010
N-myristoyltransferase inhibitors as new leads to treat sleeping sickness.
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Frearson Julie A, Brand Stephen, McElroy Stuart P, Cleghorn Laura A T, Smid Ondrej, Stojanovski Laste, Price Helen P, Guther M Lucia S, Torrie Leah S, Robinson David A, Hallyburton Irene, Mpamhanga Chidochangu P, Brannigan James A, Wilkinson Anthony J, Hodgkinson Michael, Hui Raymond, Qiu Wei, Raimi Olawale G, van Aalten Daan M F, Brenk Ruth, Gilbert Ian H, Read Kevin D, Fairlamb Alan H, Ferguson Michael A J, Smith Deborah F, Wyatt Paul G
Аннотация
African sleeping sickness or human African trypanosomiasis, caused by Trypanosoma brucei spp., is responsible for approximately 30,000 deaths each year. Available treatments for this disease are poor, with unacceptable efficacy and safety profiles, particularly in the late stage of the disease when the parasite has infected the central nervous system. Here we report the validation of a molecular target and the discovery of associated lead compounds with the potential to address this lack of suitable treatments. Inhibition of this target-T. brucei N-myristoyltransferase-leads to rapid killing of trypanosomes both in vitro and in vivo and cures trypanosomiasis in mice. These high-affinity inhibitors bind into the peptide substrate pocket of the enzyme and inhibit protein N-myristoylation in trypanosomes. The compounds identified have promising pharmaceutical properties and represent an opportunity to develop oral drugs to treat this devastating disease. Our studies validate T. brucei N-myristoyltransferase as a promising therapeutic target for human African trypanosomiasis.