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Validating and exploiting inositol phosphoryl ceramide synthase as a novel herbicide target


Project Description

With the global population predicted to continue rising there is a need for more efficient food production. An essential component of sustainable intensive cereal production is effective crop protection agents. However, many of the existing agents available to farmers are now threatened by the rapid growth in resistance and increasing regulatory demands. We face a future in which it will not be possible to control the rise of super weeds with existing technologies. This multidisciplinary project embracing synthetic chemistry, chemical biology, biochemistry and modern crops science seeks to validate a new mode of herbicide action together with small molecules that represent novel herbicidal structures. In recent work we have identified the enzyme, inositol phosphoryl ceramide synthase, plays a key regulatory role in sphingolipid synthesis. Disruption of this enzyme in whole plant assays leads to an accumulation of ceramide and a triggering of programmed cell death. As such the enzyme represents a potential new herbicide target. A medium throughput screen of the Bayer Crop Science identified four structural classes of enzyme inhibitors that affected the enzyme in either monocots or dicots but not both. This project will build on this exciting position, exploring these hits through re-synthesis and biochemical assays and then seek to optimise the activity and selectivity though structural modifications and further validate the mode of action using enzyme assays, biophysical and metabolic studies and whole plant assays.

HOW TO APPLY
Applications should be made by emailing with a CV (including contact details of at least two academic (or other relevant) referees), and a covering letter – clearly stating your first choice project, and optionally 2nd and 3rd ranked projects, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University. Applications not meeting these criteria will be rejected.
In addition to the CV and covering letter, please email a completed copy of the Additional Details Form (Word document) to . A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.
Informal enquiries may be made to

Funding Notes

This is a 4 year BBSRC CASE studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£15,009 for 2019-20). The PhD will start in October 2020. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. Please note, there are 2 stages to the application process.

References

The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity. Sci. Rep. 2019, 9, 8083

Expression levels of inositol phosphorylceramide synthase modulate plant responses to biotic and abiotic stress in Arabidopsis thaliana. PLoS ONE 2019, 14(5): e0217087

Impact of heat and drought stress on peroxisome proliferation in quinoa. Plant Journal, 2019, 99, 1144

C‐H Activation/Metalation Approaches for the Synthesis of Indolizine Derivatives’, Eur. J. Org. Chem., 2019, https://doi.org/10.1002/ ejoc.201900608

Identification of Novel Benzoxa-2,1,3 -diazole Substituted Amino Acid Hydrazides as Potential Anti-Tubercular Agents. Molecules, 2019, 24, 811

Testing a chemical series inspired by plant stress signaling agents for herbicide safening activity’, Pest. Manag.Sci., 2018, 74, 828

Identifying inhibitors of the Leishmania inositol phosphorylceramide synthase with antiprotozoal activity using a yeast-based assay and ultra-high throughput screening platform’ Sci Rep., 2018, 8, 3938

A key role for a glutathione transferase in multiple herbicide resistance in grass weeds’, Proc. Nat. Acad. Sci., 2013, 110, 5812

A plate-based assay system for analyses and screening of the Leishmania major inositol phosphorylceramide synthase. Int. J. Biochem. Cell Biol. 2010, 42, 1553–1561

Encapsulation in lipid-core nanocapsules improves topical treatment with the potent antileishmanial compound CH8, Nanomedicine, 2020, in press

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