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 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.

scholarly journals Intrinsically cell-penetrating multivalent and multitargeting ligands for myotonic dystrophy type 1

2019 ◽  
Vol 116 (18) ◽  
pp. 8709-8714 ◽  
Author(s):  
JuYeon Lee ◽  
Yugang Bai ◽  
Ullas V. Chembazhi ◽  
Shaohong Peng ◽  
Kevin Yum ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Trinucleotide Repeat ◽  
Cell Penetrating Peptides ◽  
Cell Permeability ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Multivalent Ligands ◽  
Biological Studies ◽  
Cell Penetrating

Developing highly active, multivalent ligands as therapeutic agents is challenging because of delivery issues, limited cell permeability, and toxicity. Here, we report intrinsically cell-penetrating multivalent ligands that target the trinucleotide repeat DNA and RNA in myotonic dystrophy type 1 (DM1), interrupting the disease progression in two ways. The oligomeric ligands are designed based on the repetitive structure of the target with recognition moieties alternating with bisamidinium groove binders to provide an amphiphilic and polycationic structure, mimicking cell-penetrating peptides. Multiple biological studies suggested the success of our multivalency strategy. The designed oligomers maintained cell permeability and exhibited no apparent toxicity both in cells and in mice at working concentrations. Furthermore, the oligomers showed important activities in DM1 cells and in a DM1 liver mouse model, reducing or eliminating prominent DM1 features. Phenotypic recovery of the climbing defect in adult DM1Drosophilawas also observed. This design strategy should be applicable to other repeat expansion diseases and more generally to DNA/RNA-targeted therapeutics.

scholarly journals Methods for the Creation of Cyclic Peptide Libraries for Use in Lead Discovery

2015 ◽  
Vol 20 (5) ◽  
pp. 563-576 ◽  
Author(s):  
Andrew D. Foster ◽  
James D. Ingram ◽  
Eilidh K. Leitch ◽  
Katherine R. Lennard ◽  
Eliot L. Osher ◽  
...  
Keyword(s):  
Protein Interactions ◽  
High Throughput Screening ◽  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Peptide Libraries ◽  
Successful Implementation ◽  
Protein Protein Interactions ◽  
Lead Discovery ◽  
Small Molecule Libraries ◽  
The Creation

The identification of initial hits is a crucial stage in the drug discovery process. Although many projects adopt high-throughput screening of small-molecule libraries at this stage, there is significant potential for screening libraries of macromolecules created using chemical biology approaches. Not only can the production of the library be directly interfaced with a cell-based assay, but these libraries also require significantly fewer resources to generate and maintain. In this context, cyclic peptides are increasingly viewed as ideal scaffolds and have proven capability against challenging targets such as protein-protein interactions. Here we discuss a range of methods used for the creation of cyclic peptide libraries and detail examples of their successful implementation.

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 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 Intracellular delivery of therapeutic antibodies into specific cells using antibody-peptide fusions

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Julie Gaston ◽  
Nicolas Maestrali ◽  
Guilhem Lalle ◽  
Marie Gagnaire ◽  
Alessandro Masiero ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Cell Penetrating Peptides ◽  
Therapeutic Modality ◽  
Therapeutic Antibodies ◽  
Cell Penetration ◽  
C Terminus ◽  
Macromolecular Drugs ◽  
Cell Penetrating ◽  
Intracellular Compartments ◽  
Intracellular Targets

AbstractBecause of their favorable properties as macromolecular drugs, antibodies are a very successful therapeutic modality for interfering with disease-relevant targets in the extracellular space or at the cell membrane. However, a large number of diseases involve cytosolic targets and designing antibodies able to efficiently reach intracellular compartments would expand the antibody-tractable conditions. Here, we genetically fused cell penetrating peptides (CPPs) at various positions to an antibody targeting cancer cells, evaluated the developability features of the resulting antibody-peptide fusions and the ability of selected constructs to reach the cytosol. We first determined positions in the IgG structure that were permissive to CPP incorporation without destabilizing the antibody. Fusing CPPs to the C-terminus of the light chain and either before or after the hinge had the least effect on antibody developability features. These constructs were further evaluated for cell penetration efficiency. Two out of five tested CPPs significantly enhanced antibody penetration into the cytosol, in particular when fused before or after the hinge. Finally, we demonstrate that specific antibody binding to the cell surface target is necessary for efficient cell penetration of the CPP-antibody fusions. This study provides a solid basis for further exploration of therapeutic antibodies for intracellular targets.

Backbone-Cyclized Peptides: A Critical Review

2018 ◽  
Vol 18 (7) ◽  
pp. 526-555 ◽  
Author(s):  
Samuel J.S. Rubin ◽  
Nir Qvit
Keyword(s):  
Biological Activity ◽  
Cyclic Peptide ◽  
Recombinant Expression ◽  
Building Blocks ◽  
Cell Permeability ◽  
Side Chain ◽  
Building Unit ◽  
Cyclic Peptide Synthesis ◽  
Backbone Cyclization ◽  
Conformation Stability

Backbone-cyclized peptides and peptidomimetics integrate the biological activity and pharmacological features necessary for successful research tools and therapeutics. In general, these structures demonstrate improved maintenance of bioactive conformation, stability and cell permeability compared to their linear counterparts, while maintaining support for a variety of side chain chemistries. We explain how backbone cyclization and cycloscan techniques allow scientists to cyclize linear peptides with retained or enhanced biological activity and improved drug-like features. We discuss head-to-tail (Cterminus to N-terminus), building unit-to-tail, building unit-to-side chain, building unit-to-building unit, and building unit-to-head backbone cyclization, with examples of building blocks, such as Nα-(ω- thioalkylene), Nα-(ω-aminoalkylene) and Nα-(ω-carboxyalkylene) units. We also present several methods for recombinant expression of backbone-cyclized peptides, including backbone cyclic peptide synthesis using recombinant elements (bcPURE), phage display and induced peptidyl-tRNA drop-off. Moreover, natural backbone-cyclized peptides are also produced by cyanobacteria, plants and other organisms; several of these compounds have been developed and commercialized for therapeutic applications, which we review. Backbone-cyclized peptides and peptidomimetics comprise a growing share of the pharmaceutical industry and will be applied to additional problems in the near future.

scholarly journals Predicting Cell-Penetrating Peptides: Building and Interpreting Random Forest based prediction Models

2020 ◽  
Author(s):  
Shilpa Yadahalli ◽  
Chandra S. Verma
Keyword(s):  
Random Forest ◽  
Prediction Models ◽  
Feature Space ◽  
Cell Penetrating Peptides ◽  
Amino Acid Sequences ◽  
Machine Learning Algorithms ◽  
Biologically Active ◽  
Cell Permeability ◽  
Ensemble Machine Learning ◽  
Cell Penetrating

AbstractTargeting intracellular pathways with peptide drugs is becoming increasingly desirable but often limited in application due to their poor cell permeability. Understanding cellular permeability of peptides remains a major challenge with very little structure-activity relationship known. Fortunately, there exist a class of peptides called Cell-Penetrating Peptides (CPPs), which have the ability to cross cell membranes and are also capable of delivering biologically active cargo into cells. Discovering patterns that make peptides cell-permeable have a variety of applications in drug delivery. In the current study, we build prediction models for CPPs exploring features covering a range of properties based on amino acid sequences, using Random forest classifiers which are often more interpretable than other ensemble machine learning algorithms. While obtaining prediction accuracies of ~96%, we also interpret our prediction models using TreeInterpreter, LIME and SHAP to decipher the contributions of important features and optimal feature space for CPP class. We propose that our work might offer an intuitive guide for incorporating features that impart cell-penetrability into the design of novel CPPs.

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