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|a dc
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|a Bird, Gregory H.
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|a Massachusetts Institute of Technology. Department of Biological Engineering
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|a Massachusetts Institute of Technology. Department of Biology
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|a Rezaei Araghi, Raheleh
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|a Jenson, Justin Michael
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|a Grant, Robert A
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|a Keating, Amy E
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|a Ryan, Jeremy A.
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|a Godes, Marina
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|a Pritz, Jonathan R.
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|a Letai, Anthony
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|a Walensky, Loren D.
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|a Rezaei Araghi, Raheleh
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|a Jenson, Justin Michael
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|a Grant, Robert A
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|a Keating, Amy E.
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|a Iterative optimization yields Mcl-1-targeting stapled peptides with selective cytotoxicity to Mcl-1-dependent cancer cells
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|b National Academy of Sciences (U.S.),
|c 2018-10-15T17:25:06Z.
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|z Get fulltext
|u http://hdl.handle.net/1721.1/118480
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|a Bcl-2 family proteins regulate apoptosis, and aberrant interactions of overexpressed antiapoptotic family members such as Mcl-1 promote cell transformation, cancer survival, and resistance to chemotherapy. Discovering potent and selective Mcl-1 inhibitors that can relieve apoptotic blockades is thus a high priority for cancer research. An attractive strategy for disabling Mcl-1 involves using designer peptides to competitively engage its binding groove, mimicking the structural mechanism of action of native sensitizer BH3-only proteins. We transformed Mcl-1-binding peptides into α-helical, cell-penetrating constructs that are selectively cytotoxic to Mcl-1-dependent cancer cells. Critical to the design of effective inhibitors was our introduction of an all-hydrocarbon cross-link or "staple" that stabilizes α-helical structure, increases target binding affinity, and independently confers binding specificity for Mcl-1 over related Bcl-2 family paralogs. Two crystal structures of complexes at 1.4 Å and 1.9 Å resolution demonstrate how the hydrophobic staple induces an unanticipated structural rearrangement in Mcl-1 upon binding. Systematic sampling of staple location and iterative optimization of peptide sequence in accordance with established design principles provided peptides that target intracellular Mcl-1. This work provides proof of concept for the development of potent, selective, and cell-permeable stapled peptides for therapeutic targeting of Mcl-1 in cancer, applying a design and validation work-flow applicable to a host of challenging biomedical targets. Keywords: stapled peptide; Mcl-1; apoptosis; BH3 mimetic; inhibitor
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|a United States. Department of Energy (Contract DE-AC02-06CH11357)
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|a National Institutes of Health (U.S.) (Grant R01 GM110048)
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|a Article
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|t Proceedings of the National Academy of Sciences
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