Rapid Optimization of Mcl-1 Inhibitors using Stapled Peptide Libraries Including Non-Natural Side Chains
Alpha helices form a critical part of the binding interface for many protein-protein interactions, and chemically stabilized synthetic helical peptides can be effective inhibitors of such helix-mediated complexes. In particular, hydrocarbon stapling of peptides to generate constrained helices can im...
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| Format: | Article |
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American Chemical Society (ACS)
2018
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| Online Access: | http://hdl.handle.net/1721.1/116641 https://orcid.org/0000-0001-7594-1823 https://orcid.org/0000-0002-3327-1283 https://orcid.org/0000-0003-4074-8980 |
| _version_ | 1826210334429413376 |
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| author | Letai, Anthony Rezaei Araghi, Raheleh Ryan, Jeremy Adam Keating, Amy E. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Letai, Anthony Rezaei Araghi, Raheleh Ryan, Jeremy Adam Keating, Amy E. |
| author_sort | Letai, Anthony |
| collection | MIT |
| description | Alpha helices form a critical part of the binding interface for many protein-protein interactions, and chemically stabilized synthetic helical peptides can be effective inhibitors of such helix-mediated complexes. In particular, hydrocarbon stapling of peptides to generate constrained helices can improve binding affinity and other peptide properties, but determining the best stapled peptide variant often requires laborious trial and error. Here, we describe the rapid discovery and optimization of a stapled-helix peptide that binds to Mcl-1, an antiapoptotic protein that is overexpressed in many chemoresistant cancers. To accelerate discovery, we developed a peptide library synthesis and screening scheme capable of identifying subtle affinity differences among Mcl-1-binding stapled peptides. We used our method to sample combinations of non-natural amino-acid substitutions that we introduced into Mcl-1 inhibitors in the context of a fixed helix-stabilizing hydrocarbon staple that increased peptide helical content and reduced proteolysis. Peptides discovered in our screen contained surprising substitutions at sites that are conserved in natural binding partners. Library-identified peptide M3d is the most potent molecule yet tested for selectively triggering mitochondrial permeabilization in Mcl-1 dependent cell lines. Our library approach for optimizing helical peptide inhibitors can be readily applied to the study of other biomedically important targets. |
| first_indexed | 2024-09-23T14:48:09Z |
| format | Article |
| id | mit-1721.1/116641 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T14:48:09Z |
| publishDate | 2018 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/1166412022-10-01T22:35:23Z Rapid Optimization of Mcl-1 Inhibitors using Stapled Peptide Libraries Including Non-Natural Side Chains Letai, Anthony Rezaei Araghi, Raheleh Ryan, Jeremy Adam Keating, Amy E. Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Rezaei Araghi, Raheleh Ryan, Jeremy Adam Keating, Amy E. Alpha helices form a critical part of the binding interface for many protein-protein interactions, and chemically stabilized synthetic helical peptides can be effective inhibitors of such helix-mediated complexes. In particular, hydrocarbon stapling of peptides to generate constrained helices can improve binding affinity and other peptide properties, but determining the best stapled peptide variant often requires laborious trial and error. Here, we describe the rapid discovery and optimization of a stapled-helix peptide that binds to Mcl-1, an antiapoptotic protein that is overexpressed in many chemoresistant cancers. To accelerate discovery, we developed a peptide library synthesis and screening scheme capable of identifying subtle affinity differences among Mcl-1-binding stapled peptides. We used our method to sample combinations of non-natural amino-acid substitutions that we introduced into Mcl-1 inhibitors in the context of a fixed helix-stabilizing hydrocarbon staple that increased peptide helical content and reduced proteolysis. Peptides discovered in our screen contained surprising substitutions at sites that are conserved in natural binding partners. Library-identified peptide M3d is the most potent molecule yet tested for selectively triggering mitochondrial permeabilization in Mcl-1 dependent cell lines. Our library approach for optimizing helical peptide inhibitors can be readily applied to the study of other biomedically important targets. National Institute of General Medical Sciences (U.S.) (Award R01GM110048) 2018-06-26T18:00:22Z 2018-06-26T18:00:22Z 2016-02 2015-12 2018-06-26T17:42:59Z Article http://purl.org/eprint/type/JournalArticle 1554-8929 1554-8937 http://hdl.handle.net/1721.1/116641 Rezaei Araghi, Raheleh et al. “Rapid Optimization of Mcl-1 Inhibitors Using Stapled Peptide Libraries Including Non-Natural Side Chains.” ACS Chemical Biology 11, 5 (February 2016): 1238–1244 © 2016 American Chemical Society https://orcid.org/0000-0001-7594-1823 https://orcid.org/0000-0002-3327-1283 https://orcid.org/0000-0003-4074-8980 http://dx.doi.org/10.1021/ACSCHEMBIO.5B01002 ACS Chemical Biology Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) PMC |
| spellingShingle | Letai, Anthony Rezaei Araghi, Raheleh Ryan, Jeremy Adam Keating, Amy E. Rapid Optimization of Mcl-1 Inhibitors using Stapled Peptide Libraries Including Non-Natural Side Chains |
| title | Rapid Optimization of Mcl-1 Inhibitors using Stapled Peptide Libraries Including Non-Natural Side Chains |
| title_full | Rapid Optimization of Mcl-1 Inhibitors using Stapled Peptide Libraries Including Non-Natural Side Chains |
| title_fullStr | Rapid Optimization of Mcl-1 Inhibitors using Stapled Peptide Libraries Including Non-Natural Side Chains |
| title_full_unstemmed | Rapid Optimization of Mcl-1 Inhibitors using Stapled Peptide Libraries Including Non-Natural Side Chains |
| title_short | Rapid Optimization of Mcl-1 Inhibitors using Stapled Peptide Libraries Including Non-Natural Side Chains |
| title_sort | rapid optimization of mcl 1 inhibitors using stapled peptide libraries including non natural side chains |
| url | http://hdl.handle.net/1721.1/116641 https://orcid.org/0000-0001-7594-1823 https://orcid.org/0000-0002-3327-1283 https://orcid.org/0000-0003-4074-8980 |
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