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Developing greener alternatives for peptide synthesis


Department of Chemistry

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About the Project

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. 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 phase peptide synthesis, thus solving the first problem (Green Chem. 2017, 19, 1685–1691). We also showed that a mixed solvent comprised of propylene carbonate and 2,2,5,5-tetramethyloxolane could give better swelling of Merrifield resin and hence higher yields in solid phase peptide synthesis than either individual solvent (Chem. Eur. J. 2019, 25, 4951–4964). However, not all protected amino acid derivatives and coupling agents are soluble in propylene carbonate or its mixtures 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 whilst 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 pharmaceutically important peptides and peptides with difficult sequences to demonstrate its effectiveness.

All Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills: https://www.york.ac.uk/chemistry/postgraduate/idtc/

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: https://www.york.ac.uk/chemistry/ed/.

You should expect hold or expect to achieve the equivalent of at least a UK upper second class degree in Chemistry or a related subject. Please check the entry requirements for your country: https://www.york.ac.uk/study/international/your-country/

Funding Notes

This project is open to students from any country who can fund their own studies.

The Department of Chemistry at the University of York is pleased to offer Wild Fund Scholarships. Applications are welcomed from those who meet the PhD entry criteria from any country outside the UK. Scholarships will be awarded on supervisor support, academic merit, country of origin, expressed financial need and departmental strategy. For further details and deadlines, please see our website: https://www.york.ac.uk/chemistry/postgraduate/research/funding/wild/
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