These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
A Phage-Compatible Strategy to Access Macrocyclic Peptides Featuring Asymmetric Molecular Scaffolds as Cyclization Units
preprintsubmitted 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.