A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors

Justin R. Harrison, Stephen Brand, Victoria Smith, David A. Robinson, Stephen Thompson, Alasdair Smith, Kenneth Davies, Ngai Mok, Leah S. Torrie, Iain Collie, Irene Hallyburton, Suzanne Norval, Frederick R. C. Simeons, Laste Stojanovski, Julie A. Frearson, Ruth Brenk, Paul G. Wyatt, Ian H. Gilbert (Lead / Corresponding author), Kevin D. Read (Lead / Corresponding author)

Research output: Contribution to journalArticle

14 Citations (Scopus)
168 Downloads (Pure)

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 languageEnglish
Pages (from-to)8374–8389
Number of pages16
JournalJournal of Medicinal Chemistry
Volume61
Issue number18
DOIs
Publication statusPublished - 12 Sep 2018

Fingerprint Dive into the research topics of 'A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors'. Together they form a unique fingerprint.

  • Profiles

    Cite this