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We demonstrate that the multicomponent reaction\u2010based stapling is an effective strategy for the development of \u03b1\u2010helical peptides with highly potent dual antagonistic action of MDM2 and MDMX binding p53. Such a potent inhibitory activity of p53\u2010MDM2\/X interactions was assessed by fluorescence polarization, microscale thermophoresis, and 2D NMR, while several cocrystal structures with MDM2 were obtained. This MCR stapling protocol proved efficient and versatile in terms of diversity generation at the staple, as evidenced by the incorporation of both <jats:italic>exo<\/jats:italic>\u2010 and <jats:italic>endo<\/jats:italic>\u2010cyclic hydrophobic moieties at the side chain cross\u2010linkers. The interaction of the Ugi\u2010staple fragments with the target protein was demonstrated by crystallography.<\/jats:p>","DOI":"10.1002\/anie.201916257","type":"journal-article","created":{"date-parts":[[2020,1,15]],"date-time":"2020-01-15T19:27:36Z","timestamp":1579116456000},"page":"5235-5241","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Multicomponent Peptide Stapling as a Diversity\u2010Driven Tool for the Development of Inhibitors of Protein\u2013Protein Interactions"],"prefix":"10.1002","volume":"59","author":[{"given":"Manuel G.","family":"Ricardo","sequence":"first","affiliation":[{"name":"Faculty of Chemistry, Center for Natural Product Research University of Havana  Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ameena M.","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Drug Design group, University of  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacek","family":"Plewka","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry Jagiellonian University  Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa","family":"Surmiak","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry Jagiellonian University  Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beata","family":"Labuzek","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry Jagiellonian University  Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantinos G.","family":"Neochoritis","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Drug Design group, University of  Groningen The Netherlands"},{"name":"Department of Chemistry University of  Crete Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Atmaj","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Drug Design group, University of  Groningen The Netherlands"},{"name":"Faculty of Chemistry Jagiellonian University  Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukasz","family":"Skalniak","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry Jagiellonian University  Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Drug Design group, University of  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tad A.","family":"Holak","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry Jagiellonian University  Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Groves","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Drug Design group, University of  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel G.","family":"Rivera","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Center for Natural Product Research University of Havana  Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9923-8873","authenticated-orcid":false,"given":"Alexander","family":"D\u00f6mling","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Drug Design group, University of  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,2,6]]},"reference":[{"key":"e_1_2_6_1_1","first-page":"3","volume-title":"Methods in Enzymology","author":"Verdine G. 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