ArticleACS chemical biology2016
Rapid Optimization of Mcl-1 Inhibitors using Stapled Peptide Libraries Including Non-Natural Side Chains.
Article in ACS chemical biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 43 citations in OpenAlex.
- Sequence-based prediction of the intrinsic solubility of peptides containing non-natural amino acids.Nature communications · 2023Article
- Rapid Evaluation of Staple Placement in Stabilized α Helices Using Bacterial Surface Display.ACS chemical biology · 2023Article
- Peptides from human BNIP5 and PXT1 and non-native binders of pro-apoptotic BAK can directly activate or inhibit BAK-mediated membrane permeabilization.Structure (London, England : 1993) · 2023Article
- Rational Design of Peptide-Based Inhibitors Disrupting Protein-Protein Interactions.Frontiers in chemistry · 2021Review
- Rational Design of Right-Handed Heterogeneous Peptidomimetics as Inhibitors of Protein-Protein Interactions.Journal of medicinal chemistry · 2020Article
- Peptide Folding and Binding Probed by Systematic Non-canonical Mutagenesis.Frontiers in molecular biosciences · 2020Review
- Constrained Peptides with Fine-Tuned Flexibility Inhibit NF-Y Transcription Factor Assembly.Angewandte Chemie (International ed. in English) · 2019Article
- A new strategy for the in vitro selection of stapled peptide inhibitors by mRNA display.Chemical communications (Cambridge, England) · 2019Article
- Nonproteinogenic deep mutational scanning of linear and cyclic peptides.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Differential Effects of βAngewandte Chemie (International ed. in English) · 2018Article
- Engineered protein scaffolds as leads for synthetic inhibitors of protein-protein interactions.Current opinion in chemical biology · 2018Review
- Iterative optimization yields Mcl-1-targeting stapled peptides with selective cytotoxicity to Mcl-1-dependent cancer cells.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- IKKγ-Mimetic Peptides Block the Resistance to Apoptosis Associated with Kaposi's Sarcoma-Associated Herpesvirus Infection.Journal of virology · 2017Article
- Structure-Based Design of Non-natural Macrocyclic Peptides That Inhibit Protein-Protein Interactions.Journal of medicinal chemistry · 2017Article
- Article
- Targeting intracellular protein-protein interactions with cell-permeable cyclic peptides.Current opinion in chemical biology · 2017Review
- Enriching Peptide Libraries for Binding Affinity and Specificity Through Computationally Directed Library Design.Methods in molecular biology (Clifton, N.J.) · 2017Article
- Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer.Signal transduction and targeted therapyArticle
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.