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Citation

BibTex format

@article{Bell:2012:10.1371/journal.pntd.0001625,
author = {Bell, AS and Mills, JE and Williams, GP and Brannigan, JA and Wilkinson, AJ and Parkinson, T and Leatherbarrow, RJ and Tate, EW and Holder, AA and Smith, DF},
doi = {10.1371/journal.pntd.0001625},
journal = {PLOS Neglected Tropical Diseases},
title = {Selective Inhibitors of Protozoan Protein N-myristoyltransferases as Starting Points for Tropical Disease Medicinal Chemistry Programs},
url = {http://dx.doi.org/10.1371/journal.pntd.0001625},
volume = {6},
year = {2012}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Inhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal andtrypanosome infections, using species-specific inhibitors. In order to identify inhibitors of protozoan NMTs, we chose toscreen a diverse subset of the Pfizer corporate collection against Plasmodium falciparum and Leishmania donovani NMTs.Primary screening hits against either enzyme were tested for selectivity over both human NMT isoforms (Hs1 and Hs2) andfor broad-spectrum anti-protozoan activity against the NMT from Trypanosoma brucei. Analysis of the screening results hasshown that structure-activity relationships (SAR) for Leishmania NMT are divergent from all other NMTs tested, a finding notpredicted by sequence similarity calculations, resulting in the identification of four novel series of Leishmania-selective NMTinhibitors. We found a strong overlap between the SARs for Plasmodium NMT and both human NMTs, suggesting thatachieving an appropriate selectivity profile will be more challenging. However, we did discover two novel series withselectivity for Plasmodium NMT over the other NMT orthologues in this study, and an additional two structurally distinctseries with selectivity over Leishmania NMT. We believe that release of results from this study into the public domain willaccelerate the discovery of NMT inhibitors to treat malaria and leishmaniasis. Our screening initiative is another example ofhow a tripartite partnership involving pharmaceutical industries, academic institutions and governmental/nongovernmentalorganisations such as Medical Research Council and Wellcome Trust can stimulate research for neglecteddiseases
AU  - Bell,AS
AU  - Mills,JE
AU  - Williams,GP
AU  - Brannigan,JA
AU  - Wilkinson,AJ
AU  - Parkinson,T
AU  - Leatherbarrow,RJ
AU  - Tate,EW
AU  - Holder,AA
AU  - Smith,DF
DO  - 10.1371/journal.pntd.0001625
PY  - 2012///
SN  - 1935-2735
TI  - Selective Inhibitors of Protozoan Protein N-myristoyltransferases as Starting Points for Tropical Disease Medicinal Chemistry Programs
T2  - PLOS Neglected Tropical Diseases
UR  - http://dx.doi.org/10.1371/journal.pntd.0001625
UR  - http://hdl.handle.net/10044/1/26849
VL  - 6
ER  -
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Prof. Ed Tate
GSK Chair in Chemical Biology
Department of Chemistry
Molecular Sciences Research Hub, White City Campus,
82 Wood Lane, London, W12 0BZ

e.tate@imperial.ac.uk
Tel: +44 (0)20 759 + ext 43752 or 45821