title: N-myristoyltransferase inhibitors as new leads to treat sleeping sickness.
abstract: 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.
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Frearson
authors.forename: Stephen
authors.initials: S
authors.lastname: Brand
authors.forename: Stuart P
authors.initials: SP
authors.lastname: McElroy
authors.forename: Laura A T
authors.initials: LA
authors.lastname: Cleghorn
authors.forename: Ondrej
authors.initials: O
authors.lastname: Smid
authors.forename: Laste
authors.initials: L
authors.lastname: Stojanovski
authors.forename: Helen P
authors.initials: HP
authors.lastname: Price
authors.forename: M Lucia S
authors.initials: ML
authors.lastname: Guther
authors.forename: Leah S
authors.initials: LS
authors.lastname: Torrie
authors.forename: David A
authors.initials: DA
authors.lastname: Robinson
authors.forename: Irene
authors.initials: I
authors.lastname: Hallyburton
authors.forename: Chidochangu P
authors.initials: CP
authors.lastname: Mpamhanga
authors.forename: James A
authors.initials: JA
authors.lastname: Brannigan
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Wilkinson
authors.forename: Michael
authors.initials: M
authors.lastname: Hodgkinson
authors.forename: Raymond
authors.initials: R
authors.lastname: Hui
authors.forename: Wei
authors.initials: W
authors.lastname: Qiu
authors.forename: Olawale G
authors.initials: OG
authors.lastname: Raimi
authors.forename: Daan M F
authors.initials: DM
authors.lastname: van Aalten
authors.forename: Ruth
authors.initials: R
authors.lastname: Brenk
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.forename: Alan H
authors.initials: AH
authors.lastname: Fairlamb
authors.forename: Michael A J
authors.initials: MA
authors.lastname: Ferguson
authors.forename: Deborah F
authors.initials: DF
authors.lastname: Smith
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000631:Aminopyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D057075:Enzyme Assays; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000469:parasitology*; D000096926:Benzenesulfonamides
chemical_list: D000217:Acyltransferases; D000631:Aminopyridines; D000977:Antiparasitic Agents; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; C549249:DDD 85646; D000096926:Benzenesulfonamides; C031280:pyrazole; C050480:glycylpeptide N-tetradecanoyltransferase