Phage-assisted, active site-directed ligand evolution of a potent and selective histone deacetylase 8 inhibitor.

ABSTRACT: Phage-assisted, active site-directed ligand evolution (PADLE) is a recently developed technique that uses an amber codon-encoded noncanonical amino acid (ncAA) as an anchor to direct phage-displayed peptides to a target for an enhanced ligand identification process. 2-Amino-8-oxodecanoic acid (Aoda) is a ketone-containing ncAA residue in the macrocyclic peptide natural product apicidin that is a pan-inhibitor of Zn²⁺ -dependent histone deacetylases (HDACs). Its ketone serves as an anchoring point to coordinate the catalytic zinc ion in HDACs. Using a previously evolved N^𝜀 -acetyl-lysyl-tRNA synthetase in combination with tRNA^Pyl , we showed that Aoda was efficiently incorporated into proteins in Escherichia coli by amber suppression. By propagating an ambe

SUBMITTER: Morse JS 

PROVIDER: S-EPMC9703592 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature