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Its ketone serves as an anchoring point to coordinate the catalytic zinc ion in HDACs. Using a previously evolved\n                    <jats:italic>N<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\ud835\udf00<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>\u2010<\/jats:italic>\n                    acetyl\u2010lysyl\u2010tRNA synthetase in combination with tRNA\n                    <jats:sup>Pyl<\/jats:sup>\n                    , we showed that Aoda was efficiently incorporated into proteins in\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    by amber suppression. By propagating an amber codon\u2010obligate phagemid library in\n                    <jats:italic>E. coli<\/jats:italic>\n                    encoding Aoda, we generated an Aoda\u2010containing phage\u2010displayed peptide library. Using this library to conduct PADLE against HDAC8 revealed a 7\u2010mer peptide GH8P01F1 with Aoda\u2010flanking amino acid residues that matched existing peptide sequences in identified HDAC8 substrates. Switching Aoda in GH8P01F1 to a more Zn\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010chelating ncAA\n                    <jats:italic>S<\/jats:italic>\n                    \u20102\u2010amino\u20108\u2010hydroxyamino\u20108\u2010oxooctanoic acid (Asuha) led to an extremely potent compound GH8HA01, which has an HDAC8\u2010inhibition\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>i<\/jats:italic>\n                    <\/jats:sub>\n                    value of 0.67\u2009nM. GH8HA01 and its 5\u2010mer truncation analogue Ac\u2010GH8HA01\n                    <jats:italic>\u0394<\/jats:italic>\n                    1\n                    <jats:italic>\u0394<\/jats:italic>\n                    7 that has an HDAC8\u2010inhibition\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>i<\/jats:italic>\n                    <\/jats:sub>\n                    value of 0.31\u2009nM are two of the most potent HDAC8 inhibitors that have been developed. Furthermore, both are highly selective against HDAC8 compared with other HDACs tested, demonstrating the great potential of using PADLE to identify highly potent and selective ligands for targets with conserved active sites among homologues.\n                  <\/jats:p>","DOI":"10.1002\/pro.4512","type":"journal-article","created":{"date-parts":[[2022,11,16]],"date-time":"2022-11-16T07:49:24Z","timestamp":1668584964000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["<scp>Phage\u2010assisted<\/scp>\n                    , active\n                    <scp>site\u2010directed<\/scp>\n                    ligand evolution of a potent and selective histone deacetylase 8 inhibitor"],"prefix":"10.1002","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4654-9379","authenticated-orcid":false,"given":"Jared S.","family":"Morse","sequence":"first","affiliation":[{"name":"Texas A&amp;M Drug Discovery Laboratory, 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