Ullrich, SvenGeorge, JosemonCoram, AlexandraMorewood, RichardNitsche, Christoph2022-10-312022-10-311433-7851http://hdl.handle.net/1885/276810Bicyclic 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.This study was supported by an Australian Research Council DECRA (DE190100015) and Discovery Project funding (DP200100348) awarded to C.N. Support by a RAMR (MAWA) grant awarded to S.U. and C.N. is gratefully acknowledged. S.U. acknowledges a Researcher Development Grant by the Royal Society of Chemistry.application/pdfen-AU© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH Gmbhttps://creativecommons.org/licenses/by-nc-nd/4.0/bicyclescyanopyridinemacrocyclizationnitrile-aminothiol reactionpeptidesamino acidspeptide hydrolasesviral nonstructural proteinswaterzika viruspeptides, cyclic2022-10-2410.1002/anie.202208400Creative Commons Attribution-NonCommercial-NoDerivs License