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Oppewal_ChemRxiv.pdf (2.62 MB)

A Phage-Compatible Strategy to Access Macrocyclic Peptides Featuring Asymmetric Molecular Scaffolds as Cyclization Units

preprint
submitted on 03.02.2021, 16:55 and posted on 04.02.2021, 13:13 by Titia Rixt Oppewal, Johan Hekelaar, Clemens Mayer
The cyclization of peptides appended onto proteins or whole bacteriophages is typically achieved via disulfide formation, the use of symmetric crosslinkers or the incorporation of noncanonical amino acids. Unfortunately, neither of these strategies is amenable toward generating libraries for the selection of macrocyclic peptides (MPs) akin to those found in nature, which often feature asymmetric molecular scaffolds as cyclization units that improve binding to their targets. To meet this challenge, we present an efficient two-step strategy to access MPs via the programmed modification of a unique cysteine residue and an N-terminal amine. We demonstrate that this approach yields MPs featuring asymmetric cyclization units from both synthetic peptides and when linear precursors are appended onto a phage-coat protein. Given that the employed conditions are compatible with phage display protocols, our work paves the way for the selection of natural-product-like MPs from randomized peptide sequences by phage display.

History

Email Address of Submitting Author

c.mayer@rug.nl

Institution

University of Groningen

Country

The Netherlands

ORCID For Submitting Author

0000-0002-6495-9873

Declaration of Conflict of Interest

The authors declare no conflict of interest

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