Automated Synthesis of Head-to-Tail Cyclic Peptides via Microwave-Enhanced SPPS

Introduction

Cyclic peptides are capable of bridging the gap of chemical space between small molecules and antibodies, allowing for the design of molecules with high binding affinity, remarkable selectivity, low toxicity, and the ability to access intracellular targets. As a result, macrocyclic peptides hold considerable promise as therapeutics for targeting traditionally undruggable biological targets. As of 2017, more than 40 cyclic peptides are used clinically. This encouraging trend for the development of cyclic peptides as drug candidates has provided an impetus for more robust synthetic methods for their preparation.

Head-to-tail cyclized peptides can be prepared by SPPS by using Fmoc-Glu-ODmab as the C-terminal amino acid. After synthesis of the linear peptide backbone, the Dmab group can be selectively deprotected using a dilute hydrazine solution. Afterwards, head-to-tail cyclization can be achieved using microwave-enhanced coupling. Application of microwave energy to the synthesis of head-to-tail cyclized peptides allows for more efficient coupling which leads to rapid synthesis times and high purity (CarboMAX^TM).