MANUEL NUÑO*, VICTOIRE LAUDE, DUNCAN GUTHRIE
Vapourtec, Bury Saint Edmunds, United Kingdom

Abstract

In recent years, fast flow solid-phase peptide synthesis (FF-SPPS) has been embraced by industry as way to quickly synthesise new peptide-based drugs for the discovery space. By applying uniform heating and inhibiting the movement of resin beads, high reaction efficiency is achieved, while also preventing β-sheet structure formation, thereby improving solubility of peptides as they are synthesised.
Using the FF-SPPS approach, protocols have been developed that work for both long peptides and for sequences where the peptides aggregate. These protocols achieve maximum cycle efficiency by flowing reagents in a single pass through the resin.
By way of example the suitability of FF-SPPS is illustrated by the synthesis of a 77-mer α-helical coiled coil peptide, with a synthesis time of under 20 hours and achieving a crude purity of ~62 %.
A further example is discussed for the linear scale up of a GLP-1 analogue where the use of FF-SPPS, results in a 300X scalability factor without further optimisation. The synthesis time for this GLP-1 analogue at 15 mmol scale is 15 hours with and crude purity of ~80 %.

Introduction
Largely, thanks to the recent success demonstrated by peptide drugs, such as Semaglutide and Tirzepatide, in the treatment of type-II diabetes and weight loss, there has been a significant shift in the pharmaceutical landscape towards peptides-based therapeutics. resulting from the improvement in the pharmacokinetic properties of peptide drugs, the peptide market is growing almost twice as fast as the “small molecule” market (1). There is now an increasing need to be able to quickly produce hundreds of grams of target peptides to satisfy the needs of pre-clinical and clinical trials. At this stage of the research cycle, time is of the essence, as short synthetic times will help maximising the life of the patent at the commercial stage of the drug.

For the synthesis of peptides in the discovery and pre-clinical development stages, scientists often rely on SPPS as a convenient route for the synthesis. Traditional batch technologies often give poor performance in situations where:

• Sequences exhibit aggregation events
• The synthesis of long peptides is necessary
• Rapid ...
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