Biocompatible and Selective Generation of Bicyclic Peptides

Bicyclic peptides possess superior properties for drug discovery; however, their chemical synthesis is not straightforward and often neither biocompatible nor fully orthogonal to all canonical amino acids. The selective reaction between 1,2‐aminothiols and 2,6‐dicyanopyridine allows direct access to complex bicyclic peptides in high yield. The process can be fully automated using standard solid‐phase peptide synthesis. Bicyclization occurs in water at physiological pH within minutes and without the need for a catalyst. The use of various linkers allows tailored bicyclic peptides with qualities such as plasma stability, conformational preorganization, and high target affinity. We demonstrate this for a bicyclic inhibitor of the Zika virus protease NS2B‐NS3 as well as for bicyclic versions of the α‐helical antimicrobial peptide aurein 1.2.