{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T05:49:52Z","timestamp":1792043392629,"version":"4.4.0"},"reference-count":68,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemBioChem"],"published-print":{"date-parts":[[2026,9,28]]},"abstract":"<jats:p>Fragment\u2010based strategies have transformed small\u2010molecule drug discovery, yet analogous approaches for selecting noncanonical amino acids (ncAAs) in peptide drug discovery remain largely unexplored. Here we introduce an NMR\u2010guided screening workflow that identifies individual ncAAs as \u201cfragments\u201d to identify privileged monomers prior to peptide library construction. Using the p53\u2013MDM2 interaction as a benchmark system, we screened a panel of tryptophan analogs and identified 6\u2010bromo and 6\u2010chloro tryptophan (6Br\u2010Trp and 6Cl\u2010Trp) as a higher\u2010affinity fragments relative to native Trp. Incorporation of 6Br\u2010Trp into a model peptide improved binding to MDM2, demonstrating that amino acid affinity translates directly to peptide\u2010level binding. We further show that 6Br\u2010Trp and 6Cl\u2010Trp can be efficiently charged onto tRNA and incorporated into peptides using the PURE translation system. In an mRNA display selection, peptides containing 6Br\u2010Trp and 6Cl\u2010Trp exhibited enhanced enrichment compared to their Trp\u2010containing counterparts. These results show ncAA fragment screening to be a front\u2010end strategy for guiding monomer selection in high\u2010throughput peptide discovery via mRNA display. ncAA screening also provides a route to bias peptide libraries toward more productive chemical space to accelerate the identification of high\u2010affinity ligands for challenging protein targets.<\/jats:p>","DOI":"10.1002\/cbic.70540","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T13:01:37Z","timestamp":1790168497000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["NMR\u2010Guided Fragment Screening Identifies Privileged Noncanonical Amino Acids for mRNA Display"],"prefix":"10.1002","volume":"27","author":[{"given":"Abdul J.","family":"Castillo","sequence":"first","affiliation":[{"name":"Department of Chemistry Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6033-194X","authenticated-orcid":false,"given":"Clark A.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Chemistry Virginia Commonwealth University  Richmond Virginia USA"},{"name":"Massey Comprehensive Cancer Center Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2846-6174","authenticated-orcid":false,"given":"Alba C.","family":"Dutra","sequence":"additional","affiliation":[{"name":"Department of Chemistry Virginia Commonwealth University  Richmond Virginia USA"},{"name":"Massey Comprehensive Cancer Center Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chelsea A.","family":"Makovsky","sequence":"additional","affiliation":[{"name":"Department of Chemistry Virginia Commonwealth University  Richmond Virginia USA"},{"name":"Massey Comprehensive Cancer Center Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep","family":"Lohan","sequence":"additional","affiliation":[{"name":"Department of Chemistry Virginia Commonwealth University  Richmond Virginia USA"},{"name":"Massey Comprehensive Cancer Center Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6894-2027","authenticated-orcid":false,"given":"Bipasana","family":"Shakya","sequence":"additional","affiliation":[{"name":"Department of Chemistry Virginia Commonwealth University  Richmond Virginia USA"},{"name":"Massey Comprehensive Cancer Center Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara H.","family":"Walters","sequence":"additional","affiliation":[{"name":"Department of Chemistry Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8304-8269","authenticated-orcid":false,"given":"Brian","family":"Fuglestad","sequence":"additional","affiliation":[{"name":"Department of Chemistry Virginia Commonwealth University  Richmond Virginia USA"},{"name":"The Center for Drug Discovery Virginia Commonwealth University  Richmond Virginia USA"},{"name":"Center for Advanced Therapeutics The Wistar Institute  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0210-1422","authenticated-orcid":false,"given":"Matthew C. T.","family":"Hartman","sequence":"additional","affiliation":[{"name":"Department of Chemistry Virginia Commonwealth University  Richmond Virginia USA"},{"name":"Massey Comprehensive Cancer Center Virginia Commonwealth University  Richmond Virginia USA"},{"name":"The Center for Drug Discovery Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2024.117830"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.2c00319"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm040031v"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.217"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/128_2011_180"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.274.5292.1531"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/1878\u20100261.13277"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2008.11.007"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201506783"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.9b00537"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2023.01.008"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1998.1843"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201007\u20105136"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092\u20108674(92)90644\u2010r"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/358080a0"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/26.15.3453"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543776.2017.1233179"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1303002110"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm3005465"},{"issue":"10","key":"e_1_2_9_21_1","first-page":"2141","article-title":"Identification of Novel Mdm2 Binding Peptides by Phage Display","volume":"13","author":"Bottger V.","year":"1996","journal-title":"Oncogene"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535\u20107163.mct\u201004\u20100342"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm990966p"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589\u2010019\u20100245\u20102"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.274.5289.948"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.1136"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10989\u2010015\u20109487\u20103"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0189379"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.25592"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2010.03.005"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/cb3005148"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2004.03.009"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/acssynbio.3c00353"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/90802"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0509219103"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M809096200"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42004\u2010025\u201001787\u20106"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2004.12.004"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.5b01034"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi990762a"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201107091"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1021\/ml900002k"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2007.07.010"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202400342"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202100299"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1515\/BC.2008.133"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth877"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.1c00391"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2022.03.012"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1c01186"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja301017y"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.201600253"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14932"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c15713"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.3c04833"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42004\u2010023\u201000898\u20102"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201108118"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5c13788"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2022.848689"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1809901115"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja0515809"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1002\/bip.23112"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1668"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1008365622798"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu830"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00197809"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.261"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1021\/acssynbio.2c00150"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2018.04.006"}],"container-title":["ChemBioChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbic.70540","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cbic.70540","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbic.70540","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T05:43:40Z","timestamp":1792043020000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cbic.70540"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,23]]},"references-count":68,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2026,9,28]]}},"alternative-id":["10.1002\/cbic.70540"],"URL":"https:\/\/doi.org\/10.1002\/cbic.70540","archive":["Portico"],"relation":{},"ISSN":["1439-4227","1439-7633"],"issn-type":[{"value":"1439-4227","type":"print"},{"value":"1439-7633","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,23]]},"assertion":[{"value":"2026-07-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70540"}}