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...

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NOTE: This preprint has been retracted by consensus from all authors.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.

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 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.

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.

scholarly journals Two decades of recent advances of Ugi reactions: synthetic and pharmaceutical applications

RSC Advances ◽  
2020 ◽  
Vol 10 (70) ◽  
pp. 42644-42681
Author(s):  
Manar Ahmed Fouad ◽  
Hamida Abdel-Hamid ◽  
Mohammed Salah Ayoup
Keyword(s):  
Natural Products ◽  
Heterocyclic Compounds ◽  
Cyclic Peptides ◽  
Ugi Reaction ◽  
Pharmaceutical Applications ◽  
Recent Advances

We highlight the recent advances of the Ugi reaction in the last two decades from 2000–2019, mainly in the synthesis of linear or cyclic peptides, heterocyclic compounds with versatile ring sizes, and natural products, as well as the enantioselective Ugi reactions.

scholarly journals Structural determinants for peptide-bond formation by asparaginyl ligases

2019 ◽  
pp. 201818568 ◽  
Author(s):  
Xinya Hemu ◽  
Abbas El Sahili ◽  
Side Hu ◽  
Kaho Wong ◽  
Yu Chen ◽  
...  
Keyword(s):  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Bond Formation ◽  
Peptide Bond ◽  
Cysteine Proteases ◽  
Peptide Bond Formation ◽  
Structural Determinants ◽  
Functional Studies ◽  
Definition Of ◽  
Neutral Conditions

Asparaginyl endopeptidases (AEPs) are cysteine proteases which break Asx (Asn/Asp)–Xaa bonds in acidic conditions. Despite sharing a conserved overall structure with AEPs, certain plant enzymes such as butelase 1 act as a peptide asparaginyl ligase (PAL) and catalyze Asx–Xaa bond formation in near-neutral conditions. PALs also serve as macrocyclases in the biosynthesis of cyclic peptides. Here, we address the question of how a PAL can function as a ligase rather than a protease. Based on sequence homology of butelase 1, we identified AEPs and PALs from the cyclic peptide-producing plants Viola yedoensis (Vy) and Viola canadensis (Vc) of the Violaceae family. Using a crystal structure of a PAL obtained at 2.4-Å resolution coupled to mutagenesis studies, we discovered ligase-activity determinants flanking the S1 site, namely LAD1 and LAD2 located around the S2 and S1′ sites, respectively, which modulate ligase activity by controlling the accessibility of water or amine nucleophile to the S-ester intermediate. Recombinantly expressed VyPAL1–3, predicted to be PALs, were confirmed to be ligases by functional studies. In addition, mutagenesis studies on VyPAL1–3, VyAEP1, and VcAEP supported our prediction that LAD1 and LAD2 are important for ligase activity. In particular, mutagenesis targeting LAD2 selectively enhanced the ligase activity of VyPAL3 and converted the protease VcAEP into a ligase. The definition of structural determinants required for ligation activity of the asparaginyl ligases presented here will facilitate genomic identification of PALs and engineering of AEPs into PALs.

Sign in / Sign up

Export Citation Format

Share Document