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The greening of peptide synthesis

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Peptide synthesis (both solution and solid state) is of fundamental importance to the pharmaceuticals sector. They are therefore expected to play a major role in the future of drug discovery. Currently there are more than 60 peptide based medicines approved for use by the US FDA, around 140 peptide drugs currently in clinical trials and over 500 in preclinical trials. Consequently the peptide medicines market is currently worth an estimated US$ 14.1 billion, and is predicted to grow to around US$ 25.4 billion by 2018. As such, there is a resurgence of interest in the synthesis of synthetic peptides. Peptide synthesis is a highly optimised and automatable process, however, this has resulted in a very ungreen process which:

• Is carried out in undesirable solvents such as DMF and dichloromethane.
• Makes extensive use of auxiliary agents (protecting groups and coupling agents) which end up as waste.
• Uses large excess of reagents.

Of these, the solvent is the largest source of waste and in recent work we have shown that propylene carbonate can be used as a green replacement for DMF and dichloromethane in both solution and solid state peptide synthesis, thus solving the first problem (Green Chem. 2017, 19, 1685–1691). However, not all protected amino acid derivatives and coupling agents are soluble in propylene carbonate and the piperidine used to deprotect Fmoc groups reacts with propylene carbonate. Therefore, the aim of this studentship will be to address the remaining issues in greening peptide synthesis, particularly:

1. The peptide coupling agent. Many currently used coupling agents (uronium salts, carbodiimides etc) are large molecules which produce large amounts of waste and significantly lower the E-factor of the process, especially if an active ester has to be used as well. Therefore, the use of greener coupling agents such as amino acid fluorides and 2-propanephosphonic anhydride will be investigated in both solution and solid state reactions.

2. The use of other nucleophiles to cleave an Fmoc group will be investigated, aiming to find one which is still effective for this purpose, but which reacts very slowly (or not at all with propylene carbonate).

3. The replacement of the Fmoc protecting group by alternative amine protecting groups will be investigated. For example, -sulfonylethyloxycarbonyl based groups may have better solubility in propylene carbonate which still being cleavable under weakly basic conditions.

The solution to each of 1-3 will be compared to conventional peptide synthesis in terms of yield, purity and epimerisation and used in the synthesis of short peptides to demonstrate its effectiveness.

All research students follow our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills. All research students take the core training package which provides both a grounding in the skills required for their research, and transferable skills to enhance employability opportunities following graduation. Core training is progressive and takes place at appropriate points throughout a student’s higher degree programme, with the majority of training taking place in Year 1. In conjunction with the Core training, students, in consultation with their supervisor(s), select training related to the area of their research.

The student appointed to this project will receive broad based training in the areas of organic synthesis, peptide chemistry and green chemistry.

The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel. Chemistry at York was the first academic department in the UK to receive the Athena SWAN Gold award, first attained in 2007 and then renewed in October 2010 and in April 2015.

Funding Notes

This project is open to students who can fund their own studies or who have been awarded a scholarship separate from this project. The Chemistry Department at York is pleased to offer Wild Fund Scholarships to those from countries outside the UK. Wild Fund Scholarships offer up to full tuition fees for those from countries from outside the European Union. EU students may also be offered £6,000 per year towards living costs. For further information see: View Website

Related Subjects

How good is research at University of York in Chemistry?

FTE Category A staff submitted: 47.06

Research output data provided by the Research Excellence Framework (REF)

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