Metal-catalysed tandem metathesis-hydrogenation reactions for the synthesis of carba analogues of cyclic peptides

2005 ◽  
Vol 83 (6-7) ◽  
pp. 875-881 ◽  
Author(s):  
Amanda N Whelan ◽  
Jomana Elaridi ◽  
Roger J Mulder ◽  
Andrea J Robinson ◽  
W Roy Jackson
Keyword(s):  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Somatostatin Analogues ◽  
Ring Closing Metathesis ◽  
Hydrogenation Reactions ◽  
Peptide Analogues ◽  
Tandem Metathesis

Dicarba cyclic peptide analogues of the cystine-containing octapeptides octreotide, lanreotide, and vapreotide, all known somatostatin analogues, have been synthesized via an on-resin homogeneous metal-catalysed sequence involving ruthenium-catalysed ring-closing metathesis followed by rhodium-catalysed hydrogenation.Key words: dicarba-analogues of cystine-containing peptides, octreotide, vapreotide, and lanreotide; tandem ring-closing metathesis and hydrogenation.

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NOTE: This preprint has been retracted by consensus from all authors.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 Design of Linear and Cyclic Mutant Analogues of Dirucotide Peptide (MBP82–98) against Multiple Sclerosis: Conformational and Binding Studies to MHC Class II

2018 ◽  
Vol 8 (12) ◽  
pp. 213 ◽  
Author(s):  
George Deraos ◽  
Eftichia Kritsi ◽  
Minos-Timotheos Matsoukas ◽  
Konstantina Christopoulou ◽  
Hubert Kalbacher ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cyclic Peptide ◽  
Human Leukocyte ◽  
Conformational Space ◽  
Peptide Ligand ◽  
Altered Peptide Ligand ◽  
Binding Studies ◽  
Peptide Analogues

Background: Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system. MS is a T cell-mediated disease characterized by the proliferation, infiltration, and attack of the myelin sheath by immune cells. Previous studies have shown that cyclization provides molecules with strict conformation that could modulate the immune system. Methods: In this study, we synthesized peptide analogues derived from the myelin basic protein (MBP)82–98 encephalitogenic sequence (dirucotide), the linear altered peptide ligand MBP82–98 (Ala91), and their cyclic counterparts. Results: The synthesized peptides were evaluated for their binding to human leukocyte antigen (HLA)-DR2 and HLA-DR4 alleles, with cyclic MBP82–98 being a strong binder with the HLA-DR2 allele and having lower affinity binding to the HLA-DR4 allele. In a further step, conformational analyses were performed using NMR spectroscopy in solution to describe the conformational space occupied by the functional amino acids of both linear and cyclic peptide analogues. This structural data, in combination with crystallographic data, were used to study the molecular basis of their interaction with HLA-DR2 and HLA-DR4 alleles. Conclusion: The cyclic and APL analogues of dirucotide are promising leads that should be further evaluated for their ability to alter T cell responses for therapeutic benefit against MS.

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 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>

scholarly journals Prevalence of antibodies against a cyclic peptide mimicking the FG loop of the human papillomavirus type 16 capsid among Tunisian women

2020 ◽  
Author(s):  
Elham Hassen ◽  
Devendra Bansal ◽  
Randa Ghdira ◽  
Anouar Chaieb ◽  
Hedi Khairi ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Human Papillomavirus ◽  
Sex Workers ◽  
Synthetic Peptide ◽  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Low Grade ◽  
Squamous Intraepithelial Lesions ◽  
Intraepithelial Lesions ◽  
Peptide Antibodies

Abstract Background In the past decade, cervical cancer has gone from being the second to the fourth most common cancer in women worldwide, but remains the second most common in developing countries. This cancer is most commonly caused by high-risk types of human papillomavirus (HPV), mainly type 16 (HPV16), which are sexually transmitted. This study aimed to investigate the usefulness of a cyclic synthetic peptide designed from the major L1 capsid protein of HPV16 for detecting anti-HPV16 antibodies. Methods We designed and synthetized a peptide that corresponds to the full sequence of the surface-exposed FG loop. We tested the antigenicity of the linear and the cyclic peptides against HPV16 L1 monoclonal antibodies. We used ELISA to detect anti-peptide antibodies in sera and cervical secretions of 179 Tunisian women, and we applied polymerase chain reaction and direct sequencing methods to detect and genotype HPV DNA. Results Both the linear and the cyclic peptides were recognized by the same neutralizing monoclonal antibodies, but the cyclic peptide was more reactive with human sera. The prevalence of the anti-peptide antibodies in sera was higher in women with low-grade squamous intraepithelial lesions (LGSIL) than in women with high-grade squamous intraepithelial lesions (HGSIL) (44% and 15%, respectively). This contrasts with HPV16 DNA prevalence. Compared to women from the general population, systemic IgG prevalence was significantly higher among sex workers (25%; P=0.002) and women with LGSIL (44%; P=0.001). In addition, systemic IgA and cervical IgG prevalence was higher among sex workers only (p=0.002 and P=0.001 respectively). We did not observe anti-peptide IgG antibodies in women with a current HPV16 infection.Conclusion Anti-peptide IgG in sera or in cervical secretions could be markers of an effective natural immunization against HPV16. This may open novel perspectives for monitoring vaccinated women and for the design of synthetic peptide-based vaccines.

A Conformational Study of Two Cyclic Peptide Analogues of ?-MSH

1993 ◽  
Vol 680 (1 The Melanotro) ◽  
pp. 517-519
Author(s):  
GEORGE FORSYTH ◽  
SARAH BRANCH ◽  
STEPHEN MOSS ◽  
LIDIA NOTARIANNI ◽  
DAVID OSGUTHORPE ◽  
...  
Keyword(s):  
Cyclic Peptide ◽  
Conformational Study ◽  
Peptide Analogues

scholarly journals Natural Cyclic Peptides as an Attractive Modality for Therapeutics: A Mini Review

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 2080 ◽  
Author(s):  
Muna Abdalla ◽  
Lyndy McGaw
Keyword(s):  
Drug Discovery ◽  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Pharmacological Properties ◽  
Biological Processes ◽  
Peptide Antibiotics ◽  
Natural Sources ◽  
Biological Targets ◽  
Naturally Occurring ◽  
Wide Range

Peptides are important biomolecules which facilitate the understanding of complex biological processes, which in turn could be serendipitous biological targets for future drugs. They are classified as a unique therapeutic niche and will play an important role as fascinating agents in the pharmaceutical landscape. Until now, more than 40 cyclic peptide drugs are currently in the market, and approximately one new cyclopeptide drug enters the market annually on average. Interestingly, the majority of clinically approved cyclic peptides are derived from natural sources, such as peptide antibiotics and human peptide hormones. In this report, the importance of cyclic peptides is discussed, and their role in drug discovery as interesting therapeutic biomolecules will be highlighted. Recently isolated naturally occurring cyclic peptides from microorganisms, sponges, and other sources with a wide range of pharmacological properties are reviewed herein.

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