scholarly journals Virtual Screening Using Combinatorial Cyclic Peptide Libraries Reveals Protein Interfaces Readily Targetable by Cyclic Peptides

2015 ◽  
Vol 55 (3) ◽  
pp. 600-613 ◽  
Author(s):  
Fergal J. Duffy ◽  
Darragh O’Donovan ◽  
Marc Devocelle ◽  
Niamh Moran ◽  
David J. O’Connell ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Peptide Libraries ◽  
Protein Interfaces

ChemInform Abstract: Head-to-Tail Cyclic Peptides and Cyclic Peptide Libraries

ChemInform ◽  
2000 ◽  
Vol 31 (47) ◽  
pp. no-no
Author(s):  
Arno F. Spatola ◽  
Peteris Romanovskis
Keyword(s):  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Peptide Libraries

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.

Scaffolded multiple cyclic peptide libraries for protein mimics by native chemical ligation

2014 ◽  
Vol 12 (25) ◽  
pp. 4471-4478 ◽  
Author(s):  
H. van de Langemheen ◽  
M. van Hoeke ◽  
H. C. Quarles van Ufford ◽  
J. A. W. Kruijtzer ◽  
R. M. J. Liskamp
Keyword(s):  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Peptide Libraries ◽  
Native Chemical Ligation ◽  
Chemical Ligation ◽  
Protein Mimics

The accessibility to collections, libraries and arrays of cyclic peptides is increasingly important since cyclic peptides may provide better mimics of the loop-like structures ubiquitously present in and – especially – on the surface of proteins.

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>

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 Novel Cyclic Peptides from Lethal Amanita Mushrooms through a Genome-Guided Approach

2021 ◽  
Vol 7 (3) ◽  
pp. 204
Author(s):  
Shengwen Zhou ◽  
Xincan Li ◽  
Yunjiao Lüli ◽  
Xuan Li ◽  
Zuo H. Chen ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Amino Acid Residues ◽  
Fragment Ions ◽  
Peptide Pair ◽  
A Genome ◽  
Peptide Toxins ◽  
Poisonous Mushrooms ◽  
Large Peptide

Most species in the genus Amanita are ectomycorrhizal fungi comprising both edible and poisonous mushrooms. Some species produce potent cyclic peptide toxins, such as α-amanitin, which places them among the deadliest organisms known to mankind. These toxins and related cyclic peptides are encoded by genes of the “MSDIN” family (named after the first five amino acid residues of the precursor peptides), and it is largely unknown to what extent these genes are expressed in the basidiocarps. In the present study, Amanita rimosa and Amanita exitialis were sequenced through the PacBio and Illumina techniques. Together with our two previously sequenced genomes, Amanita subjunquillea and Amanita pallidorosea, in total, 46 previously unknown MSDIN genes were discovered. The expression of over 80% of the MSDIN genes was demonstrated in A. subjunquillea. Through a combination of genomics and mass spectrometry, 12 MSDIN genes were shown to produce novel cyclic peptides. To further confirm the results, three of the cyclic peptides were chemically synthesized. The tandem mass spectrometry (MS/MS) spectra of the natural and the synthetic peptides shared a majority of the fragment ions, demonstrating an identical structure between each peptide pair. Collectively, the results suggested that the genome-guided approach is reliable for identifying novel cyclic peptides in Amanita species and that there is a large peptide reservoir in these mushrooms.

scholarly journals Cyclic peptide drugs approved in the last two decades (2001-2021)

2021 ◽  
Author(s):  
Huiya Zhang ◽  
Shiyu Chen
Keyword(s):  
Small Molecules ◽  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Peptide Drugs ◽  
Pharmaceutical Applications ◽  
Therapeutic Properties

In contrast to the major families of small molecules and antibodies, cyclic peptides, as a family of synthesizable macromolecules, have distinct biochemical and therapeutic properties for pharmaceutical applications. Cyclic peptide-based...

scholarly journals Macrocyclic Peptides as Allosteric Inhibitors of Nicotinamide N-Methyltransferase (NNMT)

2020 ◽  
Author(s):  
Matthijs J. van Haren ◽  
Yurui Zhang ◽  
Ned Buijs ◽  
Vito Thijssen ◽  
Davide Sartini ◽  
...  
Keyword(s):  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Peptide Inhibitors ◽  
Allosteric Inhibitors ◽  
Disease States ◽  
Potent Inhibition ◽  
Macrocyclic Peptides ◽  
Diabetes And Obesity ◽  
Substrate Competition

<p>Nicotinamide <i>N</i>-methyltransferase (NNMT) methylates nicotinamide to form 1-methylnicotinamide using <i>S</i>-adenosyl-l-methionine (SAM) as the methyl donor. The complexity of the role of NNMT in healthy and disease states is slowly being elucidated and provides indication that NNMT may be an interesting therapeutic target for a variety of diseases including cancer, diabetes, and obesity. Most inhibitors of NNMT described to date are structurally related to one or both of its substrates. In search of structurally diverse NNMT inhibitors, an mRNA display screening technique was used to identify macrocyclic peptides which bind to NNMT. Several of the cyclic peptides identified in this manner show potent inhibition of NNMT with IC<sub>50</sub> values as low as 229 nM. Interestingly, substrate competition experiments reveal that these cyclic peptide inhibitors are noncompetitive with either SAM or NA indicating they may be the first allosteric inhibitors reported for NNMT.</p>

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