scholarly journals Peptide Stapling Improves the Sustainability of a Peptide-Based Chimeric Molecule That Induces Targeted Protein Degradation

2021 ◽  
Vol 22 (16) ◽  
pp. 8772
Author(s):  
Hidetomo Yokoo ◽  
Nobumichi Ohoka ◽  
Mami Takyo ◽  
Takahito Ito ◽  
Keisuke Tsuchiya ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Estrogen Receptor Alpha ◽  
Cell Penetrating Peptides ◽  
Side Chain ◽  
Binding Peptide ◽  
Stapled Peptide ◽  
Chimeric Peptide ◽  
Cell Penetrating ◽  
Natural Amino Acids ◽  
Peptide Stapling

Peptide-based target protein degradation inducers called PROTACs/SNIPERs have low cell penetrability and poor intracellular stability as drawbacks. These shortcomings can be overcome by easily modifying these peptides by conjugation with cell penetrating peptides and side-chain stapling. In this study, we succeeded in developing the stapled peptide stPERML-R7, which is based on the estrogen receptor alpha (ERα)-binding peptide PERML and composed of natural amino acids. stPERML-R7, which includes a hepta-arginine motif and a hydrocarbon stapling moiety, showed increased α-helicity and similar binding affinity toward ERα when compared with those of the parent peptide PERML. Furthermore, we used stPERML-R7 to develop a peptide-based degrader LCL-stPERML-R7 targeting ERα by conjugating stPERML-R7 with a small molecule LCL161 (LCL) that recruits the E3 ligase IAPs to induce proteasomal degradation via ubiquitylation. The chimeric peptide LCL-stPERML-R7 induced sustained degradation of ERα and potently inhibited ERα-mediated transcription more effectively than the unstapled chimera LCL-PERML-R7. These results suggest that a stapled structure is effective in maintaining the intracellular activity of peptide-based degraders.

scholarly journals A preorganized β-amino acid bearing a guanidinium side chain and its use in cell-penetrating peptides

2015 ◽  
Vol 13 (20) ◽  
pp. 5617-5620 ◽  
Author(s):  
Yosuke Demizu ◽  
Makoto Oba ◽  
Koyo Okitsu ◽  
Hiroko Yamashita ◽  
Takashi Misawa ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cell Penetrating Peptides ◽  
Side Chain ◽  
Cell Penetrating ◽  
Guanidinium Group

A cyclic β-amino acid (APCGu) bearing a side-chain guanidinium group has been developed.

Cyclic, Cell-Penetrating Peptides Tailor-Made for the Creation of Peptide Libraries with Intrinsic Cell Permeability

2020 ◽  
Author(s):  
Nicolas A. Abrigo ◽  
Kara Dods ◽  
Koushambi Mitra ◽  
Kaylee Newcomb ◽  
Anthony Le ◽  
...  
Keyword(s):  
Cyclic Peptide ◽  
Cell Penetrating Peptides ◽  
Peptide Libraries ◽  
Cell Permeability ◽  
Side Chain ◽  
High Affinity ◽  
Cell Penetrating ◽  
The Creation ◽  
Intracellular Targets ◽  
Macrocyclic Peptide

<p>The discovery of high-affinity peptides to many intracellular targets has become feasible through the development of diverse macrocyclic peptide libraries. But lack of cell permeability is a key feature hampering the use of these peptides as therapeutics. Here, we develop a set of small, cyclic peptide carriers that efficiently carry cargoes into the cytosol. These peptides are cyclized via side-chain alkylation, which makes them ideal for the creation of diverse mRNA or phage-displayed libraries with intrinsic cell permeability.</p>

Cyclic, Cell-Penetrating Peptides Tailor-Made for the Creation of Peptide Libraries with Intrinsic Cell Permeability

2020 ◽  
Author(s):  
Nicolas A. Abrigo ◽  
Kara Dods ◽  
Koushambi Mitra ◽  
Kaylee Newcomb ◽  
Anthony Le ◽  
...  
Keyword(s):  
Cyclic Peptide ◽  
Cell Penetrating Peptides ◽  
Peptide Libraries ◽  
Cell Permeability ◽  
Side Chain ◽  
High Affinity ◽  
Cell Penetrating ◽  
The Creation ◽  
Intracellular Targets ◽  
Macrocyclic Peptide

<p>The discovery of high-affinity peptides to many intracellular targets has become feasible through the development of diverse macrocyclic peptide libraries. But lack of cell permeability is a key feature hampering the use of these peptides as therapeutics. Here, we develop a set of small, cyclic peptide carriers that efficiently carry cargoes into the cytosol. These peptides are cyclized via side-chain alkylation, which makes them ideal for the creation of diverse mRNA or phage-displayed libraries with intrinsic cell permeability.</p>

scholarly journals Construction of histidine-containing hydrocarbon stapled cell penetrating peptides for in vitro and in vivo delivery of siRNAs

2018 ◽  
Vol 9 (15) ◽  
pp. 3820-3827 ◽  
Author(s):  
Soonsil Hyun ◽  
Yoonhwa Choi ◽  
Ha Neul Lee ◽  
Changki Lee ◽  
Donghoon Oh ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Mouse Skin ◽  
Cell Penetrating Peptides ◽  
Stapled Peptide ◽  
Efficient Gene ◽  
Cell Penetrating ◽  
In Vivo Delivery

A hydrocarbon stapled peptide, LKH-stEK, promotes delivery of nanomolar siRNAs leading to efficient gene silencing in mouse skin.

scholarly journals Oligoalanine helical callipers for cell penetration

2018 ◽  
Vol 54 (50) ◽  
pp. 6919-6922 ◽  
Author(s):  
Marta Pazo ◽  
Marisa Juanes ◽  
Irene Lostalé-Seijo ◽  
Javier Montenegro
Keyword(s):  
Amino Acids ◽  
Rational Design ◽  
Chemical Space ◽  
Cell Penetrating Peptides ◽  
Short Peptides ◽  
Cell Penetration ◽  
Basic Amino Acids ◽  
Cell Penetrating ◽  
Natural Amino Acids

Even for short peptides that are enriched in basic amino acids, the large chemical space that can be spanned by combinations of natural amino acids hinders the rational design of cell penetrating peptides.

SynB3 conjugated QBP1 passes blood-brain barrier models and inhibits polyQ protein aggregation

2021 ◽  
Vol 29 ◽  
Author(s):  
Lingyan Zuo ◽  
Weiqian Li ◽  
Jifang Shi ◽  
Yingzhen Su ◽  
Hongyan Shuai ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Blood Brain Barrier ◽  
Cell Penetrating Peptides ◽  
Brain Barrier ◽  
Polyglutamine Diseases ◽  
Binding Peptide ◽  
Blood Brain ◽  
Cell Penetrating ◽  
Pass Through ◽  
Polyglutamine Protein

Background: Polyglutamine diseases are degenerative diseases in the central nervous system caused by CAG trinucleotide repeat expansion which encodes polyglutamine tracts, leading to the misfolding of pathological proteins. Small peptides can be designed to prevent polyglutamine diseases by inhibiting the polyglutamine protein aggregation, for example, polyglutamine binding peptide 1(QBP1). However, the transportation capability of polyglutamine binding peptide 1 across the blood-brain barrier is less efficient. We hypothesized whether its therapeutic effect could be improved by increasing the rate of membrane penetration. Objectives: The objective of the study was to explore whether polyglutamine binding peptide 1 conjugated cell-penetrating peptides could pass through the blood-brain barrier and inhibit the aggregation of polyglutamine proteins. Methods: n order to investigate the toxic effects, we constructed a novel stable inducible PC12 cells to express Huntington protein that either has 11 glutamine repeats or 63 glutamine repeats to mimic wild type and polyglutamine expand Huntington protein, respectively. Both SynB3 and TAT conjugated polyglutamine binding peptide 1 was synthesized, respectively, and we tested their capabilities to pass through a Trans-well system and subsequently studied the counteractive effects on polyglutamine protein aggregation. Results: The conjugation of cell-penetrating peptides to SynB3 and TAT enhanced the transportation of polyglutamine binding peptide 1 across the mono-cell layer and ameliorated polyglutamine-expanded Huntington protein aggregation; moreover, SynB3 showed better delivery efficiency than TAT. Interestingly, it has been observed that polyglutamine binding peptide 1 specifically inhibited polyglutamine-expanded protein aggregation rather than affected other amyloidosis proteins, for example, β-Amyloid. Conclusion: Our study indicated that SynB3 could be an effective carrier for polyglutamine binding peptide 1 distribution through the blood-brain barrier model and ameliorate the formation of polyglutamine inclusions, thus SynB3 conjugated polyglutamine binding peptide 1 could be considered as a therapeutic candidate for polyglutamine diseases.

Enzyme-Activatable Cell-Penetrating Peptides through a Minimal Side Chain Modification

2015 ◽  
Vol 26 (5) ◽  
pp. 850-856 ◽  
Author(s):  
Saskia A. Bode ◽  
Morten B. Hansen ◽  
Roy A. J. F. Oerlemans ◽  
Jan C. M. van Hest ◽  
Dennis W. P. M. Löwik
Keyword(s):  
Cell Penetrating Peptides ◽  
Side Chain ◽  
Cell Penetrating

scholarly journals Combination of Gemcitabine with Cell-Penetrating Peptides: A Pharmacokinetic Approach Using In Silico Tools

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 693
Author(s):  
Ferreira ◽  
Lapa ◽  
Vale
Keyword(s):  
Prediction Models ◽  
Cell Penetrating Peptides ◽  
New Principal ◽  
Wide Range ◽  
Property Scale ◽  
Cell Penetrating ◽  
Penetration Ability ◽  
Z Scores ◽  
Principal Property ◽  
Natural Amino Acids

Gemcitabine is an anticancer drug used to treat a wide range of solid tumors and is a first line treatment for pancreatic cancer. Our group has previously developed novel conjugates of gemcitabine with cell-penetrating peptides (CPP), and here we report some preliminary data regarding the pharmacokinetics of gemcitabine, two gemcitabine-CPP conjugates and respective CPP gathered from GastroPlus™, and analyze these results considering our previous evaluation of gemcitabine release and conjugates’ bioactivity. Additionally, seeking to shed some light on the relation between the penetration ability of CPP and their physicochemical properties, chemical descriptors for the 20 natural amino acids were calculated, a new principal property scale (z-scale) was created and CPP prediction models were developed, establishing quantitative structure-activity relationships (QSAR). The z-scores of the peptides conjugated with gemcitabine are presented and analyzed with the aforementioned data.

scholarly journals Novel Orthogonally Hydrocarbon-Modified Cell-Penetrating Peptide Nanoparticles Mediate Efficient Delivery of Splice-Switching Antisense Oligonucleotides In Vitro and In Vivo

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1046
Author(s):  
Safa Bazaz ◽  
Tõnis Lehto ◽  
Rahel Tops ◽  
Olof Gissberg ◽  
Dhanu Gupta ◽  
...  
Keyword(s):  
Antisense Oligonucleotides ◽  
Cell Penetrating Peptides ◽  
Cell Penetrating Peptide ◽  
Efficient Delivery ◽  
Cell Penetrating ◽  
Peptide Nanoparticles ◽  
Therapeutic Compounds ◽  
Peptide Stapling

Splice-switching therapy with splice-switching oligonucleotides (SSOs) has recently proven to be a clinically applicable strategy for the treatment of several mis-splice disorders. Despite this, wider application of SSOs is severely limited by the inherently poor bioavailability of SSO-based therapeutic compounds. Cell-penetrating peptides (CPPs) are a class of drug delivery systems (DDSs) that have recently gained considerable attention for improving the uptake of various oligonucleotide (ON)-based compounds, including SSOs. One strategy that has been successfully applied to develop effective CPP vectors is the introduction of various lipid modifications into the peptide. Here, we repurpose hydrocarbon-modified amino acids used in peptide stapling for the orthogonal introduction of hydrophobic modifications into the CPP structure during peptide synthesis. Our data show that α,α-disubstituted alkenyl-alanines can be successfully utilized to introduce hydrophobic modifications into CPPs to improve their ability to formulate SSOs into nanoparticles (NPs), and to mediate high delivery efficacy and tolerability both in vitro and in vivo. Conclusively, our results offer a new flexible approach for the sequence-specific introduction of hydrophobicity into the structure of CPPs and for improving their delivery properties.

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