N-myristoyltransferase inhibitors as new leads to treat sleeping sickness.
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.
Frearson
Julie A
JA
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
Brand
Stephen
S
McElroy
Stuart P
SP
Cleghorn
Laura A T
LA
Smid
Ondrej
O
Stojanovski
Laste
L
Price
Helen P
HP
Guther
M Lucia S
ML
Torrie
Leah S
LS
Robinson
David A
DA
Hallyburton
Irene
I
Mpamhanga
Chidochangu P
CP
Brannigan
James A
JA
Wilkinson
Anthony J
AJ
Hodgkinson
Michael
M
Hui
Raymond
R
Qiu
Wei
W
Raimi
Olawale G
OG
van Aalten
Daan M F
DM
Brenk
Ruth
R
Gilbert
Ian H
IH
Read
Kevin D
KD
Fairlamb
Alan H
AH
Ferguson
Michael A J
MA
Smith
Deborah F
DF
Wyatt
Paul G
PG
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
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