Display Selection of Exotic Macrocyclic Peptides Expressed under a Radically Reprogrammed 23 Amino Acid Genetic Code

Citations Over TimeTop 10% of 2018 papers

Abstract

Bioactive naturally occurring macrocyclic peptides often exhibit a strong bias for hydrophobic residues. Recent advances in in vitro display technologies have made possible the identification of potent macrocyclic peptide ligands to protein targets of interest. However, such approaches have so far been restricted to using libraries composed of peptides containing mixtures of hydrophobic and hydrophilic/charged amino acids encoded by the standard genetic code. In the present study, we have demonstrated ribosomal expression of exotic macrocyclic peptides under a radically reprogrammed, relatively hydrophobic, genetic code, comprising 12 proteinogenic and 11 nonproteinogenic amino acids. Screening of this library for affinity to the interleukin-6 receptor (IL6R) as a case study successfully identified exotic macrocyclic peptide ligands with high affinity, validating the feasibility of this approach for the discovery of relatively hydrophobic exotic macrocyclic peptide ligands.

Related Papers

• → Expanding the genetic code(2001)204 cited
• → Evolution of the Genetic Code by Incorporation of Amino Acids that Improved or Changed Protein Function(2013)34 cited
• → First arrived, first served: competition between codons for codon-amino acid stereochemical interactions determined early genetic code assignments(2020)7 cited
• → Genetic code preferentially conserves long‐range interactions among the amino acids(1989)6 cited
• Unnatural amino acid incorporation for genetic code expansion in mammalian cells(2011)