Thioether-stapled macrocyclic inhibitors of the EH domain of EHD1

Kamens, Alissa J.; Mientkiewicz, Kaley M; Eisert, Robyn J.; Walz, Jenna A.; Mace, Charles R.; Kritzer, Joshua A.

doi:10.1016/j.bmc.2017.09.007

Cited by 5 publications

(6 citation statements)

References 32 publications

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“…In many cases, stapled α‐helices have a greater extent of secondary structure, improved affinity and selectivity, improved cell penetration, and increased resistance to biological degradation . Applying stapling strategies to nonhelical peptides is significantly more challenging, but we and others have applied “diversity‐oriented stapling” methods to improve pharmacological properties of nonhelical peptides . These approaches do not assume a specific secondary structure, and thus are applicable to peptides that bind their targets in extended conformations such as FYCO1.…”

Section: Resultsmentioning

confidence: 99%

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Stapled Peptide Inhibitors of Autophagy Adapter LC3B

et al. 2020

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A growing body of evidence suggests that autophagy inhibition enhances the effectiveness of chemotherapy, especially in difficult-to-treat cancers. Existing autophagy inhibitors are primarily lysosomotropic agents. More specific autophagy inhibitors are highly sought-after. The microtubule-associated protein 1A/1B light chain 3B protein, LC3B, is an adapter protein that mediates key protein-protein interactions at several points in autophagy pathways. In this work, we used a known peptide ligand as a starting point to develop improved LC3B inhibitors. We obtained structure-activity relationships that quantify the binding contributions of peptide termini, individual charged residues, and hydrophobic interactions. Based on these data, we used artificial amino acids and diversity-oriented stapling to improve affinity and resistance to biological degradation, while maintaining or improving LC3B affinity and selectivity. These peptides represent the highest-affinity LC3B-selective ligands reported to date, and they will be useful tools for further elucidation of LC3B's role in autophagy and in cancer.

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Section: Resultsmentioning

confidence: 99%

“…Notably, most peptide stapling strategies are limited to helical motifs. Because LIR motifs bind LC3B in an extended conformation, we applied an innovative diversity‐oriented stapling strategy that does not assume any specific secondary structure …”

Section: Introductionmentioning

confidence: 99%

Stapled Peptide Inhibitors of Autophagy Adapter LC3B

et al. 2020

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“…[72,73] Applying stapling strategies to non-helical peptides is significantly more challenging, but we and others have applied "diversity-oriented stapling" methods to improve pharmacological properties of non-helical peptides. [60][61][62][63][64][65][66][67][68] These approaches do not assume a specific secondary structure, and thus are applicable to peptides that bind their targets in extended conformations such as FYCO1.…”

Section: Resultsmentioning

confidence: 99%

“…Because LIR motifs bind LC3B in an extended conformation, we applied an innovative diversity-oriented stapling strategy that does not assume any specific secondary structure. [60][61][62][63][64][65][66][67][68]…”

Section: Introductionmentioning

confidence: 99%

Stapled Peptide Inhibitors of Autophagy Adapter LC3B

et al. 2020

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For natural ligands of the human autophagy adaptor protein LC3B, the key recognition motif binds in an extended conformation (upper left). We report extensive structure–activity relationships for this important protein–protein interaction. We also used this information to design an artificial “staple” (shown in orange) that improves the binding and biological properties of the ligand peptides. More information can be found in the full paper by J. A. Kritzer et al.

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“…It is, however, not always straightforward to incorporate two unnatural amino acids in a peptide sequence. Therefore, strategies using one unnatural and one naturally occurring amino acid functionality (thereby combining a degree of selectivity with ease of synthesis) have gained increasing attention, such as the formation of a thioether [16] between a specifically located Cys residue and a second residue featuring an alkylating moiety, or peptide macrocyclization via reaction of a noncanonical aldehyde moiety and the peptide N terminus [17].…”

Section: Introductionmentioning

confidence: 99%

Pyrrole-Mediated Peptide Cyclization Identified through Genetically Reprogrammed Peptide Synthesis

et al. 2018

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Flexible in vitro translation (FIT) was used as a screening method to uncover a new methodology for peptide constraining based on the attack of a nucleophilic side-chain functionality onto an oxidized furylalanine side chain. A set of template peptides, each containing furylalanine as furan-modified amino acid and a nucleophilic residue (Cys, His, Lys, Arg, Ser, or Tyr), was produced through FIT. The translation mixtures were treated with N-bromosuccinimide (NBS) to achieve selective furan oxidation and subsequent MALDI analysis demonstrated Lys and Ser as promising residues for cyclisation. Solid-phase peptide synthesis (SPPS) was used to synthesize suitable amounts of material for further in-depth analysis and characterisation. It was found that in the case of the peptide containing lysine next to a furylalanine residue, a one-pot oxidation and reduction reaction leads to the generation of a cyclic peptide featuring a pyrrole moiety as cyclisation motif, resulting from the attack of the lysine side chain onto the oxidized furylalanine side chain. Structural evidence was provided via NMR and the generality of the methodology was explored. We hereby expand the scope of our previously developed furan-based peptide labeling and crosslinking strategy.

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Thioether-stapled macrocyclic inhibitors of the EH domain of EHD1

Cited by 5 publications

References 32 publications

Stapled Peptide Inhibitors of Autophagy Adapter LC3B

Stapled Peptide Inhibitors of Autophagy Adapter LC3B

Stapled Peptide Inhibitors of Autophagy Adapter LC3B

Pyrrole-Mediated Peptide Cyclization Identified through Genetically Reprogrammed Peptide Synthesis

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