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 2,6dicyanopyridine 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.
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.
Bizyklische Peptide sind aufgrund ihrer überragenden Eigenschaften für die Arzneimittelforschung von hoher Bedeutung. Ihre chemische Darstellung ist jedoch kompliziert und zudem häufig weder biokompatibel noch orthogonal zu allen kanonischen Aminosäuren. Die selektive Reaktion zwischen 1,2-Aminothiolen und 2,6-Dicyanpyridin ermöglicht die Synthese komplexer, bizyklischer Peptide in hoher Ausbeute. Mit Hilfe der etablierten Festphasenpeptidsynthese kann dieser Prozess vollständig automatisiert werden. Die Bizyklisierung ist katalysatorfrei und erfolgt bei physiologischem pH-Wert in Wasser binnen Minuten. Verschiedene Bindeglieder ermöglichen die Herstellung maßgeschneiderter bizyklischer Peptide, die Vorzüge wie Plasmastabilität, strukturelle Vororganisation und hohe Zielstrukturaffinität aufweisen. Dies veranschaulichen wir anhand eines bizyklischen Hemmstoffs der Zikavirus-Protease, sowie mit Hilfe bizyklischer Versionen des α-helikalen, antimikrobiellen Peptids Aurein 1.2.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.