Abstract
Crystallography has guided the hybridization of two series of Trypanosoma brucei N-myristoyltransferase (NMT) inhibitors, leading to a novel highly selective series. The effect of combining the selectivity enhancing elements from two pharmacophores is shown to be additive and has led to compounds that have greater than 1000-fold selectivity for TbNMT vs HsNMT. Further optimization of the hybrid series has identified compounds with significant trypanocidal activity capable of crossing the blood-brain barrier. By using CF-1 mdr1a deficient mice, we were able to demonstrate full cures in vivo in a mouse model of stage 2 African sleeping sickness. This and previous work provides very strong validation for NMT as a drug target for human African trypanosomiasis in both the peripheral and central nervous system stages of disease.
Original language | English |
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Pages (from-to) | 8374–8389 |
Number of pages | 16 |
Journal | Journal of Medicinal Chemistry |
Volume | 61 |
Issue number | 18 |
DOIs | |
Publication status | Published - 12 Sep 2018 |
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A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors. / Harrison, Justin R.; Brand, Stephen; Smith, Victoria; Robinson, David A.; Thompson, Stephen; Smith, Alasdair; Davies, Kenneth; Mok, Ngai; Torrie, Leah S.; Collie, Iain; Hallyburton, Irene; Norval, Suzanne; Simeons, Frederick R. C.; Stojanovski, Laste; Frearson, Julie A.; Brenk, Ruth; Wyatt, Paul G.; Gilbert, Ian H. (Lead / Corresponding author); Read, Kevin D. (Lead / Corresponding author).
In: Journal of Medicinal Chemistry, Vol. 61, No. 18, 12.09.2018, p. 8374–8389.Research output: Contribution to journal › Article
TY - JOUR
T1 - A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors
AU - Harrison, Justin R.
AU - Brand, Stephen
AU - Smith, Victoria
AU - Robinson, David A.
AU - Thompson, Stephen
AU - Smith, Alasdair
AU - Davies, Kenneth
AU - Mok, Ngai
AU - Torrie, Leah S.
AU - Collie, Iain
AU - Hallyburton, Irene
AU - Norval, Suzanne
AU - Simeons, Frederick R. C.
AU - Stojanovski, Laste
AU - Frearson, Julie A.
AU - Brenk, Ruth
AU - Wyatt, Paul G.
AU - Gilbert, Ian H.
AU - Read, Kevin D.
N1 - Funding for this work was provided by the Wellcome Trust (Grants WT077705 and WT094090 and Strategic Award WT083481).
PY - 2018/9/12
Y1 - 2018/9/12
N2 - Crystallography has guided the hybridization of two series of Trypanosoma brucei N-myristoyltransferase (NMT) inhibitors, leading to a novel highly selective series. The effect of combining the selectivity enhancing elements from two pharmacophores is shown to be additive and has led to compounds that have greater than 1000-fold selectivity for TbNMT vs HsNMT. Further optimization of the hybrid series has identified compounds with significant trypanocidal activity capable of crossing the blood-brain barrier. By using CF-1 mdr1a deficient mice, we were able to demonstrate full cures in vivo in a mouse model of stage 2 African sleeping sickness. This and previous work provides very strong validation for NMT as a drug target for human African trypanosomiasis in both the peripheral and central nervous system stages of disease.
AB - Crystallography has guided the hybridization of two series of Trypanosoma brucei N-myristoyltransferase (NMT) inhibitors, leading to a novel highly selective series. The effect of combining the selectivity enhancing elements from two pharmacophores is shown to be additive and has led to compounds that have greater than 1000-fold selectivity for TbNMT vs HsNMT. Further optimization of the hybrid series has identified compounds with significant trypanocidal activity capable of crossing the blood-brain barrier. By using CF-1 mdr1a deficient mice, we were able to demonstrate full cures in vivo in a mouse model of stage 2 African sleeping sickness. This and previous work provides very strong validation for NMT as a drug target for human African trypanosomiasis in both the peripheral and central nervous system stages of disease.
U2 - 10.1021/acs.jmedchem.8b00884
DO - 10.1021/acs.jmedchem.8b00884
M3 - Article
C2 - 30207721
VL - 61
SP - 8374
EP - 8389
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 18
ER -