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Cited by 433Chemical Synthesis and AnalysisBiochemical and Structural CharacterizationSupramolecular Self-Assembly in Materials

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Stapled Peptides for Intracellular Drug Targets

Verdine, Gregory L., Hilinski, Gerard J.·2012·Methods in Enzymology
DOI 10.1016/b978-0-12-396962-0.00001-x
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Abstract

Proteins that engage in intracellular interactions with other proteins are widely considered among the most biologically appealing yet chemically intractable targets for drug discovery. The critical interaction surfaces of these proteins typically lack the deep hydrophobic involutions that enable potent, selective targeting by small organic molecules, and their localization within the cell puts them beyond the reach of protein therapeutics. Considerable interest has therefore arisen in next-generation targeting molecules that combine the broad target recognition capabilities of protein therapeutics with the robust cell-penetrating ability of small molecules. One type that has shown promise in early-stage studies is hydrocarbon-stapled α-helical peptides, a novel class of synthetic miniproteins locked into their bioactive α-helical fold through the site-specific introduction of a chemical brace, an all-hydrocarbon staple. Stapling can greatly improve the pharmacologic performance of peptides, increasing their target affinity, proteolytic resistance, and serum half-life while conferring on them high levels of cell penetration through endocytic vesicle trafficking. Here, we discuss considerations crucial to the successful design and evaluation of potent stapled peptide interactions, our intention being to facilitate the broad application of this technology to intractable targets of both basic biologic interest and potential therapeutic value.

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Metadata

Authors
Verdine, G. L., & Hilinski, G. J.
Affiliations
Harvard University (US)
ORCID
Verdine, Gregory L.
Venue
Methods in Enzymology
Publisher
Elsevier
Published
2012
Volume
503
Pages
3-33
ISSN
0076-6879 (ISSN-L)
DOI
10.1016/b978-0-12-396962-0.00001-x
OpenAlex
W137428939
Cited by
433
References
6
Citations by year
2026: 9 · 2025: 16 · 2024: 18 · 2023: 15 · 2022: 25 · 2021: 35 · 2020: 36 · 2019: 42 · 2018: 32 · 2017: 43 · 2016: 33 · 2015: 44 · 2014: 39 · 2013: 35 · 2012: 8
FWCI
70.49
Type
book chapter
Language
en
Open access
closed
Locations
  • Methods in enzymology on CD-ROM/Methods in enzymology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
  • Physical Sciences › Materials Science › Biomaterials › Supramolecular Self-Assembly in Materials
Keywords
stapled peptides, protein-protein interaction, cell-penetrating peptides, peptide design, endosomal trafficking, protease resistance, serum half-life, therapeutic proteins
MeSH terms
Amino Acid Sequence, Animals, Cell Membrane Permeability, Flow Cytometry, Half-Life, Humans, Hydrocarbons, Molecular Sequence Data, Structure-Activity Relationship, Substrate Specificity, Drug Delivery Systems, Protein Structure, Secondary, Protein Folding, Protein Transport, Protein Interaction Domains and Motifs, Protein Stability, Cell-Penetrating Peptides, Proteolysis

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