The exchange of just a few amino acids, chosen using a novel algorithm, can create unusually stable proteins suitable for pharmaceutical applications, report UK researchers.

The exchange of just a few amino acids, chosen with the help of a novel algorithm, can create unusually stable proteins suitable for pharmaceutical applications, report UK researchers.

The pharmaceutical application of peptides and proteins holds much promise but has been limited by the tendency of polypeptides to form insoluble aggregates during storage or in the body. 

The team led by Jes?s Zurdo at the University of Cambridge set out to improve the properties of calcitonin, a peptide hormone that promotes the incorporation of calcium ions in bones and is used to treat osteoporosis. 



The human protein is prone to aggregation and the formation of amyloid fibrils, so the corresponding protein from salmon is currently preferred as a drug, even though it can cause severe side effects. Zurdo’s team focused on preventing human calcitonin from aggregating by exchanging as few amino acid residues as possible. 

The researchers created more than 600 theoretical sequence variants, each based on no more than six exchanges that were predicted to enhance solubility and stability, while leaving the biological activity intact. They tested the tendency of the peptide variants to aggregate in silico, using an algorithm they developed previously.

This screening resulted in the identification of three promising candidates, which were synthesized and tested in comparison with the human and salmon variants of the hormone, using standard in vitro tests for aggregation and interaction with the calcitonin receptor. All the variants presented significantly improved stability over the human hormone, and the best candidate even outperformed the currently used salmon preparation both in stability and in biological activity, thus offering an attractive candidate for drug development. 

Zurdo, who co-founded a company called Zyentia with Chris Dobson at the University of Cambridge’s chemistry department to make commercial use of their expertise in protein misfolding and aggregation, sees a bright pharmaceutical future.

’We are in the process of applying this strategy to a number of biopharmaceuticals whose application in therapy is largely limited due to their aggregation problems,’ said Zurdo, ’and hope to raise the interest of pharmaceutical and biotechnological partners that would be interested in licensing this technology (or reengineered variants), or engage in collaborations to improve their existing molecules.’ Michael Gross