Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia.
Angew Chem Int Ed Engl. 2022 Oct 24;61(43):e202208400. doi: 10.1002/anie.202208400. Epub 2022 Aug 22.
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.
双环肽具有优越的药物发现特性；然而，它们的化学合成并不简单，通常既不具有生物相容性，也不完全与所有典型氨基酸正交。1,2-氨基硫醇与 2,6-二氰基吡啶之间的选择性反应允许以高产率直接获得复杂的双环肽。该过程可以使用标准固相肽合成完全自动化。双环化在生理 pH 值的水中在几分钟内发生，无需催化剂。使用各种接头可以定制具有血浆稳定性、构象预组织和高靶亲和力等特性的双环肽。我们以 Zika 病毒蛋白酶 NS2B-NS3 的双环抑制剂以及 α-螺旋抗菌肽 aurein 1.2 的双环版本为例证明了这一点。
