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In our previous work, we demonstrated that peptide inhibitors can disrupt MYC transcription factor complexes in plants, but only at relatively high concentrations. Here, we show that a chemically defined chemocarrier overcomes this limitation and enables low-dose functional activity of peptide inhibitors in planta. To access TF\u2013cofactor interfaces, we established a multi-step, target-guided screening platform that links in vitro high-throughput assays with functional validation in plants. This workflow integrates primary and secondary AlphaScreen assays using full-length and truncated MYC constructs with a tertiary assay targeting the interaction between MYCs and the MED25 coactivator. Screening of an approved-drug library followed by structure\u2013activity optimization led to the identification of a low-toxicity aromatic derivative with potent cell-penetrating activity in Arabidopsis. Conjugation with this chemocarrier markedly enhanced the intracellular delivery and functional efficacy of multiple MYC-targeting peptide scaffolds, including cyclic and stapled peptides, resulting in over two orders of magnitude improvement in potency. This enabled robust inhibition of MYC-dependent transcriptional programs at substantially reduced concentrations, converting peptide-based inhibition from a high-dose proof-of-concept into a low-dose, functionally tractable strategy. These findings establish a practical chemical modality for accessing transcription factor\u2013cofactor interfaces in plants.<\/jats:p>","DOI":"10.1021\/acschembio.6c00523","type":"journal-article","created":{"date-parts":[[2026,8,16]],"date-time":"2026-08-16T15:01:39Z","timestamp":1786892499000},"page":"2404-2414","source":"Crossref","is-referenced-by-count":0,"title":["Chemocarrier-Enabled Peptide Inhibition of MYC-Cofactor Interactions in Plants"],"prefix":"10.1021","volume":"21","author":[{"given":"Ruiqi","family":"Liu","sequence":"first","affiliation":[{"name":"Kyoto University , , Kitashirakawa Oiwake-cho , Sakyo-ku, ,","place":["Kyoto, Japan, 606-8502"]},{"name":"Tohoku University , , 6-3 Aramaki-Aza-Aoba , Aoba-ku, ,","place":["Sendai, Japan, 980-8578"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuma","family":"Uehara","sequence":"additional","affiliation":[{"name":"Kyoto University , , Kitashirakawa Oiwake-cho , Sakyo-ku, ,","place":["Kyoto, Japan, 606-8502"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koshiki","family":"Mino","sequence":"additional","affiliation":[{"name":"RIKEN Center for Sustainable Resource Science , Hirosawa 2-1 , , ,","place":["Wako, Saitama, Japan, 351-0198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Idei","sequence":"additional","affiliation":[{"name":"RIKEN Center for Sustainable Resource Science , Hirosawa 2-1 , , ,","place":["Wako, Saitama, Japan, 351-0198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazusa","family":"Kimoto","sequence":"additional","affiliation":[{"name":"Osaka Metropolitan University , , Gakuen-cho 1-1 , Naka-ku, , ,","place":["Sakai, Osaka, Japan, 599-8570"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6230-5534","authenticated-orcid":true,"given":"Daisuke","family":"Fujiwara","sequence":"additional","affiliation":[{"name":"Osaka Metropolitan University , , Gakuen-cho 1-1 , Naka-ku, , ,","place":["Sakai, Osaka, Japan, 599-8570"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4376-5674","authenticated-orcid":true,"given":"Minoru","family":"Yoshida","sequence":"additional","affiliation":[{"name":"RIKEN Center for Sustainable Resource Science , Hirosawa 2-1 , , ,","place":["Wako, Saitama, Japan, 351-0198"]},{"name":"The University of Tokyo , , Yayoi 1-1-1 , Bunkyo-ku, ,","place":["Tokyo, Japan, 113-8657"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2305-3303","authenticated-orcid":true,"given":"Minoru","family":"Ueda","sequence":"additional","affiliation":[{"name":"Tohoku University , , 6-3 Aramaki-Aza-Aoba , Aoba-ku, ,","place":["Sendai, Japan, 980-8578"]},{"name":"Tohoku University , , 2-1-1, Katahira , Aoba-ku, ,","place":["Sendai, Japan, 980-8577"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1559-4924","authenticated-orcid":true,"given":"Yousuke","family":"Takaoka","sequence":"additional","affiliation":[{"name":"Kyoto University , , Kitashirakawa Oiwake-cho , Sakyo-ku, ,","place":["Kyoto, Japan, 606-8502"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,16]]},"reference":[{"key":"2026101511072674900_cit1","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1016\/S1369-5266(00)00107-2","article-title":"A genomic perspective on plant transcription factors","volume":"3","author":"Riechmann","year":"2000","journal-title":"Curr. 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