Bent into shape: Folded peptides to mimic protein structure and modulate protein function

Merritt, Haley I.; Sawyer, Nicholas; Arora, Paramjit S.

doi:10.1002/pep2.24145

Cited by 51 publications

(44 citation statements)

References 248 publications

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“…However, as well as previously reported EPO-derived peptides, our peptides, including ML1-h3, still are in a native form, and this study leaves enough room for the development of more advanced EPO-derived peptides. So far, chemical modifications have been established to improve the stability and bioavailability of peptide drugs with advanced synthetic chemistry [ 97 , 98 ]. Acetylation at N-terminal, cyclization of N- to C-terminal, incorporation of N-methylated or unnatural amino acid, replacement to amide bond mimetics such as thioamides, peptoids, and β-amino acids, PEGylation, and lipidation have been used for peptide drug development.…”

Section: Discussionmentioning

confidence: 99%

Second-generation non-hematopoietic erythropoietin-derived peptide for neuroprotection

Cho¹,

Yoo²,

Kim³

et al. 2022

Redox Biology

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Erythropoietin (EPO) is a well-known erythropoietic cytokine having a tissue-protective effect in various tissues against hypoxic stress, including the brain. Thus, its recombinants may function as neuroprotective compounds. However, despite considerable neuroprotective effects, the EPO-based therapeutic approach has side effects, including hyper-erythropoietic and tumorigenic effects. Therefore, some modified forms and derivatives of EPO have been proposed to minimize the side effects. In this study, we generated divergently modified new peptide analogs derived from helix C of EPO, with several amino acid replacements that interact with erythropoietin receptors (EPORs). This modification resulted in unique binding potency to EPOR. Unlike recombinant EPO, among the peptides, ML1-h3 exhibited a potent neuroprotective effect against oxidative stress without additional induction of cell-proliferation, owing to a differential activating mode of EPOR signaling. Furthermore, it inhibited neuronal death and brain injury under hypoxic stress in vitro and in an in vivo ischemic brain injury model. Therefore, the divergent modification of EPO-derivatives for affinity to EPOR could provide a basis for a more advanced and optimal neuroprotective strategy.

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Section: Discussionmentioning

confidence: 99%

Second-generation non-hematopoietic erythropoietin-derived peptide for neuroprotection

Cho¹,

Yoo²,

Kim³

et al. 2022

Redox Biology

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“…We were able to demonstrate the utility of BRC8-2 in a functional cellular assay for disruption of radiation-induced RAD51 foci formation. Strategies to further stabilize this -hairpin may involve the use of tryptophantryptophan cross-strand pairs 40 or even artificial crosslinks such as triazole 41 , to achieve an additional enhancement of binding through a reduction in conformational heterogeneity prior to complex formation (as well as improving resistance to proteolytic degradation). Our work revealed that the linker between the FxxA module and LFDE module is also likely to play a role in determining the affinity of the peptide.…”

Section: Discussionmentioning

confidence: 99%

Improved RAD51 binders through motif shuffling based on the modularity of BRC repeats

Lindenburg

Pantelejevs

Gielen

et al. 2020

Preprint

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Exchanges of protein sequence modules support leaps in function unavailable through point mutations during evolution. Here we study the role of the two RAD51-interacting modules within the eight binding BRC repeats of BRCA2. We created 64 chimeric repeats by shuffling these modules and measured their binding to RAD51. We found that certain shuffled repeats were stronger than any of the natural repeats, suggesting balancing of relative properties in BRC repeats. Surprisingly, the contribution from the two modules was poorly correlated with affinities of natural repeats, with weak BRC8 repeat containing the most effective N-terminal module. The binding of the strongest chimera, BRC8-2, to RAD51 was improved by -2.44 kCal/mol compared to the strongest natural repeat, BRC4. Crystal structure of RAD51:BRC8-2 complex shows an improved interface fit and an extended -hairpin in this repeat. BRC8-2 was shown to function in human cells, preventing the formation of nuclear foci after ionizing radiation.

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“…Even though β‐sheets occur frequently in PPIs, [4] the corresponding mimetics have been less explored as PPI inhibitors [5] . In general, most β‐sheet mimetics are based on β‐hairpin peptides which comprise two antiparallel β‐strands connected by a turn [5b, 6] . The β‐hairpin structure can be stabilized by backbone modifications within the β‐strands, β‐sheet‐inducing turn mimetics and by hairpin macrocyclization [5–7] .…”

Section: Introductionmentioning

confidence: 99%

Bicyclic β‐Sheet Mimetics that Target the Transcriptional Coactivator β‐Catenin and Inhibit Wnt Signaling

et al. 2021

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Protein complexes are defined by the three-dimensional structure of participating binding partners.K nowledge about these structures can facilitate the design of peptidomimetics which have been applied for example,a si nhibitors of protein-protein interactions (PPIs). Even though b-sheets participate widely in PPIs,t hey have only rarely served as the basis for peptidomimetic PPI inhibitors,inparticular when addressing intracellular targets.Here,wepresent the structurebased design of b-sheet mimetics targeting the intracellular protein b-catenin, ac entral component of the Wnt signaling pathway.B ased on ap rotein binding partner of b-catenin, amacrocyclic peptide was designed and its crystal structure in complex with b-catenin obtained. Using this structure,w e designed al ibrary of bicyclic b-sheet mimetics employing al ate-stage diversification strategy.S everal mimetics were identified that compete with transcription factor binding to bcatenin and inhibit Wnt signaling in cells.The presented design strategy can support the development of inhibitors for other bsheet-mediated PPIs.

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Bent into shape: Folded peptides to mimic protein structure and modulate protein function

Cited by 51 publications

References 248 publications

Second-generation non-hematopoietic erythropoietin-derived peptide for neuroprotection

Second-generation non-hematopoietic erythropoietin-derived peptide for neuroprotection

Improved RAD51 binders through motif shuffling based on the modularity of BRC repeats

Bicyclic β‐Sheet Mimetics that Target the Transcriptional Coactivator β‐Catenin and Inhibit Wnt Signaling

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