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Hence, the KIX domain has attracted considerable attention in drug discovery and development. Here, we rationally designed a KIX inhibitor using a peptide fragment corresponding to the transactivation domain (TAD) of the transcriptional activator, mixed-lineage leukemia protein (MLL). We performed theoretical saturation mutagenesis using the Rosetta software to search for mutants expected to bind KIX more tightly than the wild-type MLL TAD. Mutant peptides with higher helical propensities were selected for experimental characterization. We found that the T2857W mutant of the MLL TAD peptide had the highest binding affinity for KIX compared to the other 12 peptides designed in this study. Moreover, the peptide had a high inhibitory effect on the KIX\u2013MLL interaction with a half-maximal inhibitory concentration close to the dissociation constant for this interaction. To our knowledge, this peptide has the highest affinity for KIX among all previously reported inhibitors that target the MLL site of KIX. Thus, our approach may be useful for rationally developing helical peptides that inhibit protein\u2013protein interactions implicated in the progression of various diseases.<\/jats:p>","DOI":"10.1038\/s41598-023-32848-2","type":"journal-article","created":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T10:02:52Z","timestamp":1681812172000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Rational peptide design for inhibition of the KIX\u2013MLL interaction"],"prefix":"10.1038","volume":"13","author":[{"given":"Nao","family":"Sato","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunji","family":"Suetaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuuki","family":"Hayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1223-2242","authenticated-orcid":false,"given":"Munehito","family":"Arai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,4,18]]},"reference":[{"key":"32848_CR1","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1016\/j.cell.2011.02.016","volume":"144","author":"M Vidal","year":"2011","unstructured":"Vidal, M., Cusick, M. E. & Barabasi, A. L. Interactome networks and human disease. Cell 144, 986\u2013998. https:\/\/doi.org\/10.1016\/j.cell.2011.02.016 (2011).","journal-title":"Cell"},{"key":"32848_CR2","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.cbpa.2018.06.004","volume":"44","author":"X Ran","year":"2018","unstructured":"Ran, X. & Gestwicki, J. E. Inhibitors of protein-protein interactions (PPIs): An analysis of scaffold choices and buried surface area. Curr. Opin. Chem. Biol. 44, 75\u201386. https:\/\/doi.org\/10.1016\/j.cbpa.2018.06.004 (2018).","journal-title":"Curr. Opin. Chem. Biol."},{"key":"32848_CR3","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1016\/j.copbio.2008.06.004","volume":"19","author":"E Petsalaki","year":"2008","unstructured":"Petsalaki, E. & Russell, R. B. Peptide-mediated interactions in biological systems: New discoveries and applications. Curr. Opin. 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