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cyclization peptides

Chiara Testa, Anna Maria Papini, Michael Chorev, Paolo Rovero
The long lasting impetus to design novel modes of macrocyclization, and their implementation into a wide range of bioactive peptides, originates from their contributions to the restriction of conformational space and the stabilization of preferential bioactive conformations that support higher efficacy and binding affinity to cognate macromolecular targets, improved specificity and lowering susceptibility to enzymatic degradation processes. Introducing CuI-catalyzed azide-alkyne cycloadditon (CuAAC), a prototypical click reaction, to the field of peptide sciences as a bio-orthogonal reaction that generates a disubstituted-[1,2,3]triazol-1-yl moiety as a pseudopeptidic bond that is peptidomimetic in nature, paved the way to its wide spread application as a new and promising mode of macrocyclization...
May 17, 2018: Current Topics in Medicinal Chemistry
Samuel J S Rubin, Yftah Tal-Gan, Chaim Gilon, Nir Qvit
Protein-protein interactions (PPIs) are particularly important for controlling both physiologic and pathologic biological processes but are difficult to target due to their large and/or shallow interaction surfaces unsuitable for small molecules. Linear peptides found in nature interact with some PPIs, and protein active regions can be used to design synthetic peptide compounds for inhibition of PPIs. However, linear peptides are limited therapeutically by poor metabolic and conformational stability, which can compromise their bioactivity and half-life...
May 17, 2018: Current Topics in Medicinal Chemistry
Samuel J S Rubin, Nir Qvit
Backbone-cyclized peptides and peptidomimetics integrate the biological activity and pharmacological features necessary for successful research tools and therapeutics. In general, these structures demonstrate improved maintenance of bioactive conformation, stability and cell permeability compared to their linear counterparts, while maintaining support for a variety of side chain chemistries. We explain how backbone cyclization and cycloscan techniques allow scientists to cyclize linear peptides with retained or enhanced biological activity and improved drug-like features...
May 17, 2018: Current Topics in Medicinal Chemistry
Andrea Angelo Pierluigi Tripodi, Szilárd Tóth, Kata Nóra Enyedi, Gitta Schlosser, Gergely Szakács, Gábor Mező
Cyclic NGR peptides as homing devices are good candidates for the development of drug conjugates for targeted tumor therapy. In our previous study we reported that the Dau=Aoa-GFLGK(c[KNGRE]-GG-)-NH2 conjugate has a significant antitumor activity against both CD13+ HT-1080 human fibrosarcoma and CD13- but integrin positive HT-29 human colon adenocarcinoma cells. However, it seems that the free ε-amino group of Lys in the cycle is not necessary for the biological activity. Therefore, we developed novel cyclic NGR peptide-daunomycin conjugates in which Lys was replaced by different amino acids (Ala, Leu, Nle, Pro, Ser)...
2018: Beilstein Journal of Organic Chemistry
Clara Brieke, Miroslaw Tarnawski, Anja Greule, Max J Cryle
Cytochrome P450 enzymes perform an impressive range of oxidation reactions against diverse substrate scaffolds whilst generally maintaining a conserved tertiary structure and active site chemistry. Within secondary metabolism, P450 enzymes play widespread and important roles in performing crucial modifications of precursor molecules, with one example of the importance of such reactions being found in the biosynthesis of the glycopeptide antibiotics (GPAs). In GPA biosynthesis P450s, known as Oxy enzymes, are key players in the cyclization of the linear GPA peptide precursor, which is a process that is both essential for their antibiotic activity and is the source of the synthetic challenge of these important antibiotics...
May 3, 2018: Journal of Inorganic Biochemistry
Jonathan G Hubert, Iain A Stepek, Hidetoshi Noda, Jeffrey W Bode
Macrocyclic β-peptides were efficiently prepared using a thiadiazole-forming cyclization reaction between an α-ketoacid and a thiohydrazide. The linear β-peptide precursors were assembled from isoxazolidine monomers by α-ketoacid-hydroxylamine (KAHA) ligations with a bifunctional initiator - a process we have termed 'synthetic fermentation' due to the analogy of producing natural product-like molecules from simpler building blocks. The linear synthetic fermentation products underwent Boc-deprotection/thiadiazole-forming macrocyclization under aqueous, acidic conditions to provide the cyclic products in a one-pot process...
February 28, 2018: Chemical Science
Ivan Di Bonaventura, Stéphane Baeriswyl, Alice Capecchi, Bee-Ha Gan, Xian Jin, Thissa N Siriwardena, Runze He, Thilo Köhler, Arianna Pompilio, Giovanni Di Bonaventura, Christian van Delden, Sacha Javor, Jean-Louis Reymond
We used the concept of chemical space to explore a virtual library of bicyclic peptides formed by double thioether cyclization of a precursor linear peptide, and identified an antimicrobial bicyclic peptide (AMBP) with remarkable activity against several MDR strains of Acinetobacter baumannii and Pseudomonas aeruginosa.
May 2, 2018: Chemical Communications: Chem Comm
Sangram S Kale, Camille Villequey, Xu-Dong Kong, Alessandro Zorzi, Kaycie Deyle, Christian Heinis
Successful screening campaigns depend on large and structurally diverse collections of compounds. In macrocycle screening, variation of the molecular scaffold is important for structural diversity, but so far it has been challenging to diversify this aspect in large combinatorial libraries. Here, we report the cyclization of peptides with two chemical bridges to provide rapid access to thousands of different macrocyclic scaffolds in libraries that are easy to synthesize, screen and decode. Application of this strategy to phage-encoded libraries allowed for the screening of an unprecedented structural diversity of macrocycles against plasma kallikrein, which is important in the swelling disorder hereditary angioedema...
April 30, 2018: Nature Chemistry
Melanie Schoppet, Julien Tailhades, Ketav Kulkarni, Max J Cryle
Natural products such as the glycopeptide antibiotics (GPAs, including vancomycin and teicoplanin) are of great pharmaceutical importance due to their use against Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus. GPAs are assembled in a complex process based on nonribosomal peptide synthesis and late-stage, multistep cross-linking of the linear heptapeptide performed by cytochrome P450 monooxygenases. These P450 enzymes demonstrate varying degrees of substrate selectivity toward the linear peptide precursor, with limited information available about their tolerance regarding modifications to amino acid residues within the essential antibiotic core of the GPA...
April 30, 2018: Journal of Organic Chemistry
Minmi Jo, Sun-Woo Won, Dong Guk Lee, Jungeon Yun, Sunhong Kim, Young-Shin Kwak
4,4-Dimethyloxazolones derived from N-protected aminoisobutyric acid (AIB) are particularly known as poor electrophiles due to the steric hindrance around the carbonyl and not employed as useful intermediates for amidation whereas numerous examples have been reported to support the utility of other oxazolones in amidation. AIB is an important and strategical synthon in medicinal chemistry but the peptide bond formation of the N-protected urethane derivatives of AIB is known to be often unproductive due to the rapid formation of the stable 4,4-dimethyloxazolone via an intramolecular cyclization...
April 25, 2018: Archives of Pharmacal Research
Athanasios Lourbopoulos, Minos-Timotheos Matsoukas, Maria Katsara, George Deraos, Aggeliki Giannakopoulou, Roza Lagoudaki, Nikolaos Grigoriadis, John Matsoukas, Vasso Apostolopoulos
We report the novel synthesis of cyclic PLP139-151 (cPLP) and its application in SJL/J mice to study its encephalitogenic effects. Our results indicate that the cPLP analog is minimally encephalitogenic when administered to induce experimental autoimmune encephalomyelitis (low disease burden, minimal inflammatory, demyelinating and axonopathic pathology compared to its linear counterpart). Proliferation assays confirmed the low stimulatory potential of the cPLP compared to linPLP (2.5-fold lower proliferation) as well as inducing lower antibody responses...
December 19, 2017: Bioorganic & Medicinal Chemistry
Claudio A Álvarez, Paula A Santana, Omar Luna, Constanza Cárdenas, Fernando Albericio, María S Romero, Fanny Guzmán
Cyclotides are circular peptides found in various plant families. A cyclized backbone, together with multiple disulfide bonds, confers the peptides’ exceptional stability against protease digestion and thermal denaturation. In addition, the features of these antimicrobial molecules make them suitable for use in animal farming, such as aquaculture. Fmoc solid phase peptide synthesis on 2-chlorotrityl chlorine (CTC) resin using the “tea-bag” approach was conducted to generate the VarvA cyclotide identified previously from Viola arvensis ...
April 19, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Qi Chang, Yu-Lei Li, Xia Zhao
Samoamide A is a cyclic octapeptide rich in proline and phenylalanine residues isolated from an American Samoa marine cyanobacterium, which exhibits potent activity against H460 human non-small-cell lung cancer cells (IC50 of 1.1 μM). The first total synthesis of samoamide A was achieved by employing a strategy of a solid-phase peptide synthesis (SPPS) and a head-to-tail cyclization selecting free steric-hinrance connection sites. Then the final product was purified and identified. This strategy not only provides a basis in producing potent cytotoxic agents for drug discovery, but also provides a reference to the total synthesis of proline-rich peptides...
April 19, 2018: Journal of Asian Natural Products Research
Lara R Malins
Transition-metal catalysis has unlocked new paradigms for the late-stage modification and cyclization of peptides by harnessing the innate reactivity of proteinogenic amino acids. The field is rapidly evolving, with recent advances encompassing three fundamental areas-heteroatom couplings, decarboxylative cross-couplings, and C-H functionalizations-which have markedly extended the scope of conventional peptide modification and bioconjugation strategies. The advances outlined herein facilitate access to high-value peptide targets with promising applications in materials science and drug discovery...
April 12, 2018: Current Opinion in Chemical Biology
Florian B Zauner, Brigitta Elsasser, Elfriede Dall, Chiara Cabrele, Hans Brandstetter
Legumain is a dual-function protease peptide ligase whose activities are of great interest to researchers studying plant physiology and to biotechnological applications. However, the molecular mechanisms determining the specificities for proteolysis and ligation are unclear because structural information on the substrate recognition by a fully activated plant legumain is unavailable. Here, we present the X-ray structure of Arabidopsis thaliana legumain isoform γ (AtLEGγ) in complex with the covalent peptidic Ac-YVAD chloro methyl ketone (CMK) inhibitor targeting the catalytic cysteine...
April 8, 2018: Journal of Biological Chemistry
Xue-Jian Zhang, Xia-Ling Wu, Xiao-Wei Wang, Dong Liu, Shuguang Yang, Wen-Bin Zhang
The SpyTag/SpyCatcher reaction has emerged as a powerful way for bioconjugation, but it leaves a folded complex in the product after the formation of the isopeptide bond. To vary the location of the reactive residue and reduce the size of the complex and its potential immunogenicity, we engineer two circularly permuted SpyCatcher variants, SpyCatcher-N and SpyCatcher-NTEV, the latter of which possesses a TEV-recognition site for removal of the fragment containing the catalytic site. Surprisingly, both variants are found to be disordered in solution, yet still retain the ability to form an ordered complex upon reaction with SpyTag with second order rate constants of ~10 M-1∙ s-1...
April 6, 2018: Bioconjugate Chemistry
Xuekai Zhang, Gang Lu, Meng Sun, Madhu Mahankali, Yanfei Ma, Mingming Zhang, Wangde Hua, Yuting Hu, Qingbing Wang, Jinghuo Chen, Gang He, Xiangbing Qi, Weijun Shen, Peng Liu, Gong Chen
New methods capable of effecting cyclization, and forming novel three-dimensional structures while maintaining favourable physicochemical properties are needed to facilitate the development of cyclic peptide-based drugs that can engage challenging biological targets, such as protein-protein interactions. Here, we report a highly efficient and generally applicable strategy for constructing new types of peptide macrocycles using palladium-catalysed intramolecular C(sp3 )-H arylation reactions. Easily accessible linear peptide precursors of simple and versatile design can be selectively cyclized at the side chains of either aromatic or modified non-aromatic amino acid units to form various cyclophane-braced peptide cycles...
April 2, 2018: Nature Chemistry
Rhiannon Beard, Andy Stucki, Muriel Schmitt, Gabrielle Py, Christophe Grundschober, Antony D Gee, Edward W Tate
Oxytocin (OT) is an exciting potential therapeutic agent, but it is highly sensitive to modification and suffers extensive degradation at elevated temperature and in vivo. Here we report studies towards OT analogs with favorable selectivity, affinity and potency towards the oxytocin receptor (OTR), in addition to improving stability of the peptide by bridging the disulfide region with substituted dibromo-xylene analogs. We found a sensitive structure-activity relationship in which meta-cyclized analogs (dOTmeta ) gave highest affinity (50 nM Ki ), selectivity (34-fold), and agonist potency (34 nM EC50 , 87-fold selectivity) towards OTR...
March 12, 2018: Bioorganic & Medicinal Chemistry
Xu Yang, Ahmed E Yousef
Species that are currently listed under the genus Brevibacillus (formerly, Bacillus brevis cluster) have been a rich source of antimicrobial peptides for many decades. The first known peptide antibiotic, gramicidin, is presumed to be produced by a Brevibacillus sp. Members of the genus are widely spread in nature. They can be found in a variety of environments including intestinal tracts of animals, seawater, and soil. Some Brevibacillus strains have been used commercially as probiotics. Bioactive peptides produced by Brevibacillus spp...
March 29, 2018: World Journal of Microbiology & Biotechnology
Aline D de Araujo, Junxian Lim, Kai-Chen Wu, Yibin Xiang, Andrew C Good, Renato Skerlj, David P Fairlie
A 26-residue peptide BimBH3 binds indiscriminately to multiple oncogenic Bcl2 proteins that regulate apoptosis of cancer cells. Specific inhibition of the BimBH3-Bcl2A1 protein-protein interaction was obtained in vitro and in cancer cells by shortening the peptide to 14 residues, inserting two cyclization constraints to stabilize a water-stable α-helix, and incorporating an N-terminal acrylamide electrophile for selective covalent bonding to Bcl2A1. Mass spectrometry of trypsin-digested bands on electrophoresis gels established covalent bonding of an electrophilic helix to just one of the three cysteines in Bcl2A1, the one (Cys55) at the BimBH3-Bcl2A1 protein-protein interaction interface...
March 27, 2018: Journal of Medicinal Chemistry
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