TY - JOUR
T1 - The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity
AU - Pinneh, Elizabeth C.
AU - Mina, John G.
AU - Stark, Michael J. R.
AU - Lindell, Stephen D.
AU - Luemmen, Peter
AU - Knight, Marc R.
AU - Steel, Patrick G.
AU - Denny, Paul W.
N1 - E.C.P. was supported by a Biotechnology and Biological Research Council CASE studentship with Bayer Crop Sciences (BB/K012703/1). J.G.M. and P.W.D. were also supported by the Biotechnology and Biological Research Council (BB/M024156/1); P.W.D. and P.G.S. are also supported by the Medical Research Council (MR/P027989/1). We thank Durham University’s Wolfson Research Institute for Health and Wellbeing, and Biophysical Sciences Institute for support.
PY - 2019/5/30
Y1 - 2019/5/30
N2 - Resistance to 157 different herbicides and 88% of known sites of action has been observed, with many weeds resistant to two or more modes. Coupled with tighter environmental regulation, this demonstrates the need to identify new modes of action and novel herbicides. The plant sphingolipid biosynthetic enzyme, inositol phosphorylceramide synthase (IPCS), has been identified as a novel, putative herbicide target. The non-mammalian nature of this enzyme offers the potential of discovering plant specific inhibitory compounds with minimal impact on animals and humans, perhaps leading to the development of new non-toxic herbicides. The best characterised and most highly expressed isoform of the enzyme in the model-dicot Arabidopsis, AtIPCS2, was formatted into a yeast-based assay which was then utilized to screen a proprietary library of over 11,000 compounds provided by Bayer AG. Hits from this screen were validated in a secondary in vitro enzyme assay. These studies led to the identification of a potent inhibitor that showed selectivity for AtIPCS2 over the yeast orthologue, and activity against Arabidopsis seedlings. This work highlighted the use of a yeast-based screening assay to discover herbicidal compounds and the status of the plant IPCS as a novel herbicidal target.
AB - Resistance to 157 different herbicides and 88% of known sites of action has been observed, with many weeds resistant to two or more modes. Coupled with tighter environmental regulation, this demonstrates the need to identify new modes of action and novel herbicides. The plant sphingolipid biosynthetic enzyme, inositol phosphorylceramide synthase (IPCS), has been identified as a novel, putative herbicide target. The non-mammalian nature of this enzyme offers the potential of discovering plant specific inhibitory compounds with minimal impact on animals and humans, perhaps leading to the development of new non-toxic herbicides. The best characterised and most highly expressed isoform of the enzyme in the model-dicot Arabidopsis, AtIPCS2, was formatted into a yeast-based assay which was then utilized to screen a proprietary library of over 11,000 compounds provided by Bayer AG. Hits from this screen were validated in a secondary in vitro enzyme assay. These studies led to the identification of a potent inhibitor that showed selectivity for AtIPCS2 over the yeast orthologue, and activity against Arabidopsis seedlings. This work highlighted the use of a yeast-based screening assay to discover herbicidal compounds and the status of the plant IPCS as a novel herbicidal target.
UR - http://www.scopus.com/inward/record.url?scp=85066487185&partnerID=8YFLogxK
U2 - 10.1038/s41598-019-44544-1
DO - 10.1038/s41598-019-44544-1
M3 - Article
C2 - 31147620
SN - 2045-2322
VL - 9
SP - 1
EP - 8
JO - Scientific Reports
JF - Scientific Reports
M1 - 8083
ER -