Highly Conformationally Restricted Cyclopropane Tethers with Three-Dimensional Structural Diversity Drastically Enhance the Cell Permeability of Cyclic Peptides

2016 ◽  
Vol 23 (13) ◽  
pp. 3034-3041 ◽  
Author(s):  
Kouhei Matsui ◽  
Yasuto Kido ◽  
Ryosuke Watari ◽  
Yousuke Kashima ◽  
Yutaka Yoshida ◽  
...  
Keyword(s):  
Cyclic Peptides ◽  
Three Dimensional ◽  
Structural Diversity ◽  
Cell Permeability ◽  
Conformationally Restricted

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>

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>

scholarly journals Three-Dimensional Structures of Carbohydrates and Where to Find Them

2020 ◽  
Vol 21 (20) ◽  
pp. 7702 ◽  
Author(s):  
Sofya I. Scherbinina ◽  
Philip V. Toukach
Keyword(s):  
Experimental Data ◽  
Molecular Modeling ◽  
Computational Methods ◽  
Three Dimensional ◽  
Structural Diversity ◽  
Structural Data ◽  
Structural Features ◽  
Data Validation ◽  
Data Generation ◽  
Efficient Treatment

Analysis and systematization of accumulated data on carbohydrate structural diversity is a subject of great interest for structural glycobiology. Despite being a challenging task, development of computational methods for efficient treatment and management of spatial (3D) structural features of carbohydrates breaks new ground in modern glycoscience. This review is dedicated to approaches of chemo- and glyco-informatics towards 3D structural data generation, deposition and processing in regard to carbohydrates and their derivatives. Databases, molecular modeling and experimental data validation services, and structure visualization facilities developed for last five years are reviewed.

A novel, convenient, three-dimensional orthogonal strategy for solid-phase synthesis of cyclic peptides

1993 ◽  
Vol 34 (10) ◽  
pp. 1549-1552 ◽  
Author(s):  
Steven A. Kates ◽  
Nuria A. Solé ◽  
Charles R. Johnson ◽  
Derek Hudson ◽  
George Barany ◽  
...  
Keyword(s):  
Cyclic Peptides ◽  
Solid Phase Synthesis ◽  
Solid Phase ◽  
Three Dimensional ◽  
Phase Synthesis

scholarly journals Structural Aspects of Phenylalanylation and Quality Control in Three Major Forms of Phenylalanyl-tRNA Synthetase

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Liron Klipcan ◽  
Igal Finarov ◽  
Nina Moor ◽  
Mark G. Safro
Keyword(s):  
Quaternary Structure ◽  
Thermus Thermophilus ◽  
Three Dimensional ◽  
Structural Diversity ◽  
Structural Data ◽  
Trna Synthetase ◽  
Transfer Rnas ◽  
Trna Synthetases ◽  
Editing Activity ◽  
Structural Aspects

Aminoacyl-tRNA synthetases (aaRSs) are a canonical set of enzymes that specifically attach corresponding amino acids to their cognate transfer RNAs in the cytoplasm, mitochondria, and nucleus. The aaRSs display great differences in primary sequence, subunit size, and quaternary structure. Existence of three types of phenylalanyl-tRNA synthetase (PheRS)—bacterial (αβ)2, eukaryotic/archaeal cytosolic (αβ)2, and mitochondrial α—is a prominent example of structural diversity within the aaRSs family. Although archaeal/eukaryotic and bacterial PheRSs share common topology of the core domains and the B3/B4 interface, where editing activity of heterotetrameric PheRSs is localized, the detailed investigation of the three-dimensional structures from three kingdoms revealed significant variations in the local design of their synthetic and editing sites. Moreover, as might be expected from structural data eubacterial, Thermus thermophilus and human cytoplasmic PheRSs acquire different patterns of tRNAPhe anticodon recognition.

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