scholarly journals Improvement on Permeability of Cyclic Peptide/Peptidomimetic: Backbone N-Methylation as A Useful Tool

Marine Drugs ◽  
2021 ◽  
Vol 19 (6) ◽  
pp. 311
Author(s):  
Yang Li ◽  
Wang Li ◽  
Zhengshuang Xu
Keyword(s):  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Three Dimensional ◽  
Conformational Space ◽  
Cell Permeability ◽  
Relative Importance ◽  
Intrinsic Properties ◽  
Surface Areas ◽  
Synthetic Methodologies ◽  
Three Dimensional Configuration

Peptides have a three-dimensional configuration that can adopt particular conformations for binding to proteins, which are well suited to interact with larger contact surface areas on target proteins. However, low cell permeability is a major challenge in the development of peptide-related drugs. In recent years, backbone N-methylation has been a useful tool for manipulating the permeability of cyclic peptides/peptidomimetics. Backbone N-methylation permits the adjustment of molecule’s conformational space. Several pathways are involved in the drug absorption pathway; the relative importance of each N-methylation to total permeation is likely to differ with intrinsic properties of cyclic peptide/peptidomimetic. Recent studies on the permeability of cyclic peptides/peptidomimetics using the backbone N-methylation strategy and synthetic methodologies will be presented in this review.

scholarly journals Automated Design of Macrocycles for Therapeutic Applications: from Small Molecules to Peptides and Proteins

2020 ◽  
Author(s):  
Daniel Sindhikara ◽  
Michael Wagner ◽  
Paraskevi Gkeka ◽  
Stefan Guessregen ◽  
Garima Tiwari ◽  
...  
Keyword(s):  
Small Molecules ◽  
Cyclic Peptides ◽  
Conformational Stability ◽  
Three Dimensional ◽  
Cell Permeability ◽  
Linear Molecule ◽  
Retrospective Case ◽  
Therapeutic Modalities ◽  
Protein Interfaces ◽  
Starting Point

<div>Macrocycles and cyclic peptides are increasingly attractive therapeutic modalities as they often have </div><div>improved affinity, are able to bind to extended protein interfaces and otherwise have favorable </div><div>properties. Macrocyclization of a known binder molecule has the potential to stabilize its bioactive </div><div>conformation, improve its metabolic stability, cell permeability and in certain cases oral </div><div>bioavailability. Herein, we present an in silico approach that automatically generates, evaluates and </div><div>proposes cyclizations utilizing a library of well-established chemical reactions and reagents. Using the </div><div>three-dimensional (3D) conformation of the linear molecule in complex with a target protein as </div><div>starting point, this approach identifies attachment points, generates linkers, evaluates the </div><div>conformational landscape of suitable linkers and their geometric compatibility and ranks the resulting </div><div>molecules with respect to their predicted conformational stability and interactions with the target </div><div>protein. As we show here with several prospective and retrospective case studies, this procedure can </div><div>be applied for the macrocyclization of small molecules and peptides and even PROTACs and proteins.</div><div>The presented approach is an important step towards the enhanced utilization of macrocycles and</div><div>cyclic peptides as attractive therapeutic modalities.</div>

Amide-to-Ester Substitution Improves Membrane Permeability of a Cyclic Peptide Without Altering Its Three-Dimensional Structure

2020 ◽  
Author(s):  
Yuki Hosono ◽  
Jumpei Morimoto ◽  
Chad Townsend ◽  
Colin N. Kelly ◽  
Matthew R. Naylor ◽  
...  
Keyword(s):  
Membrane Permeability ◽  
Protein Interactions ◽  
Cyclic Peptides ◽  
Rational Design ◽  
Cyclic Peptide ◽  
Three Dimensional ◽  
Amide Bond ◽  
Cell Membrane Permeability ◽  
Dimensional Structure ◽  
Molecular Mechanics Calculations

<div> <div> <div> <p>Cyclic peptides are attractive molecules as inhibitors with high affinity and selectivity against intracellular protein-protein interactions (PPIs). On the other hand, cyclic peptides generally have low passive cell-membrane permeability, which makes it difficult to discover cyclic peptides that efficiently permeate into cells and inhibit intracellular PPIs. Here, we show that backbone amide-to-ester substitutions are useful for improving membrane permeability of peptides. Permeability in a series of model dipeptides increased upon amide-to-ester substitution. Amide-to-ester substitutions increased permeability in the same manner as amide-to-N-methyl amide substitutions, which are conventionally used for increasing permeability. Furthermore, amide-to-ester substitutions of exposed amides of a cyclic peptide successfully improved permeability. Conformational studies of the cyclic peptides using NMR and molecular mechanics calculations revealed that an amide-to-ester substitution of an exposed amide bond did not affect its low-energy conformation in CDCl<sub>3</sub>, in contrast with an N-methyl amide substitution. We envision that amide-to-ester substitution will be a potentially useful strategy for rational design of bioactive peptides with high membrane permeability. </p> </div> </div> </div>

scholarly journals Three-dimensional graphene networks: synthesis, properties and applications

2014 ◽  
Vol 2 (1) ◽  
pp. 40-53 ◽  
Author(s):  
Yanfeng Ma ◽  
Yongsheng Chen
Keyword(s):  
Graphene Oxide ◽  
Three Dimensional ◽  
Porous Structures ◽  
Intrinsic Properties ◽  
Surface Areas ◽  
Synthesis Properties ◽  
Potential Applications ◽  
Specific Surface Areas ◽  
Graphene Foams ◽  
Mechanical Strengths

Abstract Recently, three-dimensional graphene/graphene oxide (GO) networks (3DGNs) in the form of foams, sponges and aerogels have attracted much attention. 3D structures provide graphene materials with high specific surface areas, large pore volumes, strong mechanical strengths and fast mass and electron transport, owing to the combination of the 3D porous structures and the excellent intrinsic properties of graphene. This review focuses on the latest advances in the preparation, properties and potential applications of 3D micro-/nano-architectures made of graphene/GO-based networks, with emphasis on graphene foams and sponges.

scholarly journals Amide-to-Ester Substitution Improves Membrane Permeability of a Cyclic Peptide Without Altering Its Three-Dimensional Structure

2020 ◽  
Author(s):  
Yuki Hosono ◽  
Jumpei Morimoto ◽  
Chad Townsend ◽  
Colin N. Kelly ◽  
Matthew R. Naylor ◽  
...  
Keyword(s):  
Membrane Permeability ◽  
Protein Interactions ◽  
Cyclic Peptides ◽  
Rational Design ◽  
Cyclic Peptide ◽  
Three Dimensional ◽  
Amide Bond ◽  
Cell Membrane Permeability ◽  
Dimensional Structure ◽  
Molecular Mechanics Calculations

<div> <div> <div> <p>Cyclic peptides are attractive molecules as inhibitors with high affinity and selectivity against intracellular protein-protein interactions (PPIs). On the other hand, cyclic peptides generally have low passive cell-membrane permeability, which makes it difficult to discover cyclic peptides that efficiently permeate into cells and inhibit intracellular PPIs. Here, we show that backbone amide-to-ester substitutions are useful for improving membrane permeability of peptides. Permeability in a series of model dipeptides increased upon amide-to-ester substitution. Amide-to-ester substitutions increased permeability in the same manner as amide-to-N-methyl amide substitutions, which are conventionally used for increasing permeability. Furthermore, amide-to-ester substitutions of exposed amides of a cyclic peptide successfully improved permeability. Conformational studies of the cyclic peptides using NMR and molecular mechanics calculations revealed that an amide-to-ester substitution of an exposed amide bond did not affect its low-energy conformation in CDCl<sub>3</sub>, in contrast with an N-methyl amide substitution. We envision that amide-to-ester substitution will be a potentially useful strategy for rational design of bioactive peptides with high membrane permeability. </p> </div> </div> </div>

scholarly journals Automated Design of Macrocycles for Therapeutic Applications: from Small Molecules to Peptides and Proteins

2020 ◽  
Author(s):  
Daniel Sindhikara ◽  
Michael Wagner ◽  
Paraskevi Gkeka ◽  
Stefan Guessregen ◽  
Garima Tiwari ◽  
...  
Keyword(s):  
Small Molecules ◽  
Cyclic Peptides ◽  
Conformational Stability ◽  
Three Dimensional ◽  
Cell Permeability ◽  
Linear Molecule ◽  
Retrospective Case ◽  
Therapeutic Modalities ◽  
Protein Interfaces ◽  
Starting Point

<div>Macrocycles and cyclic peptides are increasingly attractive therapeutic modalities as they often have </div><div>improved affinity, are able to bind to extended protein interfaces and otherwise have favorable </div><div>properties. Macrocyclization of a known binder molecule has the potential to stabilize its bioactive </div><div>conformation, improve its metabolic stability, cell permeability and in certain cases oral </div><div>bioavailability. Herein, we present an in silico approach that automatically generates, evaluates and </div><div>proposes cyclizations utilizing a library of well-established chemical reactions and reagents. Using the </div><div>three-dimensional (3D) conformation of the linear molecule in complex with a target protein as </div><div>starting point, this approach identifies attachment points, generates linkers, evaluates the </div><div>conformational landscape of suitable linkers and their geometric compatibility and ranks the resulting </div><div>molecules with respect to their predicted conformational stability and interactions with the target </div><div>protein. As we show here with several prospective and retrospective case studies, this procedure can </div><div>be applied for the macrocyclization of small molecules and peptides and even PROTACs and proteins.</div><div>The presented approach is an important step towards the enhanced utilization of macrocycles and</div><div>cyclic peptides as attractive therapeutic modalities.</div>

A Target-Based Method for Designing Heterochiral Cyclic Peptide Binders: De Novo Inhibitors of the PD-1/PD-L1 Interaction

2020 ◽  
Author(s):  
Salvador Guardiola ◽  
Monica Varese ◽  
Xavier Roig ◽  
Jesús Garcia ◽  
Ernest Giralt
Keyword(s):  
Protein Interactions ◽  
Cyclic Peptides ◽  
General Framework ◽  
Large Scale ◽  
Cyclic Peptide ◽  
De Novo ◽  
Inhibitory Effect ◽  
Original Text ◽  
Retraction Notice ◽  
Pharmaceutical Properties

<p>NOTE: This preprint has been retracted by consensus from all authors. See the retraction notice in place above; the original text can be found under "Version 1", accessible from the version selector above.</p><p><br></p><p>------------------------------------------------------------------------</p><p><br></p><p>Peptides, together with antibodies, are among the most potent biochemical tools to modulate challenging protein-protein interactions. However, current structure-based methods are largely limited to natural peptides and are not suitable for designing target-specific binders with improved pharmaceutical properties, such as macrocyclic peptides. Here we report a general framework that leverages the computational power of Rosetta for large-scale backbone sampling and energy scoring, followed by side-chain composition, to design heterochiral cyclic peptides that bind to a protein surface of interest. To showcase the applicability of our approach, we identified two peptides (PD-<i>i</i>3 and PD-<i>i</i>6) that target PD-1, a key immune checkpoint, and work as protein ligand decoys. A comprehensive biophysical evaluation confirmed their binding mechanism to PD-1 and their inhibitory effect on the PD-1/PD-L1 interaction. Finally, elucidation of their solution structures by NMR served as validation of our <i>de novo </i>design approach. We anticipate that our results will provide a general framework for designing target-specific drug-like peptides.<i></i></p>

Three-Dimensional Computerized Anthropometry of the Nose: Landmark Representation Compared to Surface Analysis

2007 ◽  
Vol 44 (3) ◽  
pp. 278-285 ◽  
Author(s):  
Virgilio F. Ferrario ◽  
Fabrizio Mian ◽  
Redento Peretta ◽  
Riccardo Rosati ◽  
Chiarella Sforza
Keyword(s):  
Three Dimensional ◽  
Digital Data ◽  
Limits Of Agreement ◽  
B Splines ◽  
Surface Areas ◽  
Using Data ◽  
Difference Volume ◽  
T Values ◽  
Plaster Models ◽  
Plaster Casts

Objective: To compare three-dimensional nasal measurements directly made on subjects to those made on plaster casts, and nasal dimensions obtained with a surface-based approach to values obtained with a landmark representation. Methods: Soft-tissue nasal landmarks were directly digitized on 20 healthy adults. Stone casts of their noses were digitized and mathematically reconstructed using nonuniform rational B-splines (NURBS) curves. Linear distances, angles, volumes and surface areas were computed using facial landmarks and NURBS-reconstructed models (surface-based approach). Results: Measurements on the stone casts were somewhat smaller than values obtained directly from subjects (differences between −0.05 and −1.58 mm). Dahlberg's statistic ranged between 0.73 and 1.47 mm. Significant (p < .05) t values were found for 4 of 15 measurements. The surface-based approach gave values 3.5 (volumes) and 2.1 (surface area) times larger than those computed with the landmark-based method. The two values were significantly related (volume, r = 0.881; surface, r = 0.924; p < .001), the resulting equations estimated actual values well (mean difference, volume −0.01 mm3, SD 1.47, area 0.05 cm2, SD 1.44); limits of agreement between −2.89 and 2.87 mm3 (volume); −2.88 and 2.78 cm2 (area). Conclusions: Considering the characteristics of the two methods, and for practical purposes, nasal distances and angles obtained on plaster models were comparable to digital data obtained directly from subjects. Surface areas and volumes were best obtained using a surface-based approach, but could be estimated using data provided by the landmark representation.

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