PhD Studentship - Synthetic Strategies for Dynamic Covalent Protein Recognition

PhD Description

We are looking for an enthusiastic and well-organized student to join a vibrant and growing research group that operates at the interface of Organic Synthesis and Chemical Biology. The project will focus on the design and synthesis of conformationally preorganised molecules (peptidomimetic foldamers) that recognise key elements of protein surfaces. These scaffolds will form a toolkit of chemical probes to target: (i) protein-protein interactions (PPIs) and; (ii) proteins prone to misfolding. Aberrant control of these systems lies at the heart of many diseases such as cancer, diabetes and neurodegeneration (Alzheimer's, Parkinson's, and others).

The Specific objectives of the project are the: (i) design, synthesis, and characterisation of new peptidomimetic foldamers; (ii) attachment of covalent warheads that can form bonds selectively with amino side-chains on the target protein; (iii) investigation of their ability to mediate the behaviour of therapeutically-relevant proteins.

Prior experience in Organic Synthesis (e.g. during a Masters project or on placement) is essential. Chemical Biology or Medicinal Chemistry experience is not required, but training in these areas will be provided for interested students.

For recent relevant publications see:

• Curr. Opin. Chem. Biol. 2018, 44, pp. 30-38.
• Chem Sci. 2016, 7, pp. 6435-6439.
• Angew. Chem. Int. Ed. 2015, 54, pp. 2649-2652.
• Angew. Chem. Int. Ed. 2014, 53, pp. 3650-3653.

Background - structure and function in Nature

The inspiration and motivation for research in the group derives from the exquisite control that Nature exerts over structure and function - at both atomic and macromolecular levels. Unmet challenges in biology and medicine stem from gaps in our understanding of the basic science underlying these processes and a shortage of chemical tools for the interrogation and manipulation of specific interactions. Proteins constitute a bio-macromolecular class of particular interest due to their essential roles in all life forms, performing myriad structural, catalytic, and signalling functions. They are critically important in numerous disease states including cancer, diabetes, and neurodegeneration.

Organic synthesis as a key tool

Our major long-term goals are to develop a deeper understanding of the structure/function relationships governing therapeutically relevant protein-protein interactions (PPIs) and protein-misfolding conditions, and to develop molecular tools for their manipulation. In our group organic synthesis and methodology are central tools allied with rigorous structural and conformational assignment by solution- and solid-phase methods (especially NMR and X-ray). Combined with techniques from the fields of supramolecular chemistry, physical organic, and chemical biology this makes for multi-disciplinary projects. We have established collaborations with experts in molecular- and cellular-biology, providing insights into the behaviour of our chemical probes in physiologically relevant settings.

Research and training environment

The group is based in the modern synthetic chemistry laboratories in the School of Chemistry on the leafy Southampton Highfield Campus. Experimental chemistry is supported by world-class MS, NMR and X-ray facilities, with expert staff in each area to help design methods and analyze data. In addition to training in practical synthetic methods the student will be supported through regular group meetings and problem sessions. Opportunities to learn chemical biology and structural biology techniques will be provided through established collaborations. There will also be opportunities for the supervision of junior co-workers, and funds available for the presentation of work at national and international conferences.

Funding and further information

The project is funded for 3 and a half years and welcomes applicants from the UK and EU who have or expect to obtain at least an upper second class degree in Chemistry or allied subjects/relevant disciplines. Funding will cover fees and a stipend at current research council rates per annum (201920 rates are £15,009).

Due to funding restrictions this position is only open to UK students and EU students who meet the RCUK eligibility criteria

Applications for a PhD in Chemistry should be submitted online at https://studentrecords.soton.ac.uk/BNNRPROD/bzsksrch.P_Search

Contact

General enquiries should be made to Sam Thompson at st3a15@soton.ac.uk . Any queries on the application process should be made to feps-pgr-apply@soton.ac.uk

Applications will be considered in the order that they are received, and the position will be considered filled when a suitable candidate has been identified

The University of Southampton and the School of Chemistry both hold Athena SWAN Silver Awards, reflecting their commitment to equality, diversity and inclusion, and particularly to gender equality.