作者: Wyatt, Paul G. ; Fang, Wenxia ; Harrison, Justin R. ; Gilbert, Ian H. ; Blair, David E. ; Robinson, David A. ; Ruda, Gian Filippo ; Torrie, Leah S. ; Lockhart, Deborah E. A. ; van Aalten, Daan M. F. ; Raimi, Olawale G.

Treatment of filamentous fungal infections relies on a limited repertoire of antifungal agents. Compounds possessing novel modes of action are urgently required. N-myristoylation is a ubiquitous modification of eukaryotic proteins. The enzyme N-myristoyltransferase (NMT) has been considered a potential therapeutic target in protozoa and yeasts. Here, we show that the filamentous fungal pathogen Aspergillus fumigatus possesses an active NMT enzyme that is essential for survival. Surprisingly, partial repression of the gene revealed downstream effects of N-myristoylation on cell wall morphology. Screening a library of inhibitors led to the discovery of a pyrazole sulphonamide compound that inhibits the enzyme and is fungicidal under partially repressive nmt conditions. Together with a crystallographic complex showing the inhibitor binding in the peptide substrate pocket, we provide evidence of NMT being a potential drug target in A. fumigatus.

2012-10-25·Journal of Medicinal Chemistry1区 · 医学

Design and Synthesis of Inhibitors of Plasmodium falciparumN-Myristoyltransferase, A Promising Target for Antimalarial Drug Discovery

1区 · 医学

Article

作者: Leatherbarrow, Robin J. ; Moss, David K. ; Tate, Edward W. ; Holder, Anthony A. ; Brzozowski, A. Marek ; Wilkinson, Anthony J. ; Brannigan, James A. ; Yu, Zhiyong

Design of inhibitors for N-myristoyltransferase (NMT), an enzyme responsible for protein trafficking in Plasmodium falciparum , the most lethal species of parasites that cause malaria, is described. Chemistry-driven optimization of compound 1 from a focused NMT inhibitor library led to the identification of two early lead compounds 4 and 25, which showed good enzyme and cellular potency and excellent selectivity over human NMT. These molecules provide a valuable starting point for further development.

2012-01-12·Journal of Medicinal Chemistry1区 · 医学

Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors

1区 · 医学

Article

作者: Brenk, Ruth ; Spinks, Daniel ; Norcross, Neil R. ; Hallyburton, Irene ; Ferguson, Michael A. J. ; Brand, Stephen ; Smith, Victoria C. ; Frearson, Julie A. ; Harrison, Justin R. ; McElroy, Stuart P. ; Stojanovski, Laste ; Cleghorn, Laura A. T. ; Wyatt, Paul G. ; Bayliss, Tracy ; Norval, Suzanne ; Fairlamb, Alan H. ; Gilbert, Ian H. ; Read, Kevin D. ; Torrie, Leah S. ; Robinson, David A.

N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report the optimization of a high throughput screening hit (1) to give a lead molecule DDD85646 (63), which has potent activity against the enzyme (IC(50) = 2 nM) and T. brucei (EC(50) = 2 nM) in culture. The compound has good oral pharmacokinetics and cures rodent models of peripheral HAT infection. This compound provides an excellent tool for validation of T. brucei NMT as a drug target for HAT as well as a valuable lead for further optimization.

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