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cyclization peptides

Shaozhou Zhu, Christopher D Fage, Julian D Hegemann, Andreas Mielcarek, Dushan Yan, Uwe Linne, Mohamed A Marahiel
Lasso peptides are a class of ribosomally synthesized and post-translationally modified peptides (RiPPs) with a unique lariat knot-like fold that endows them with extraordinary stability and biologically relevant activity. However, the biosynthetic mechanism of these fascinating molecules remains largely speculative. Generally, two enzymes (B for processing and C for cyclization) are required to assemble the unusual knot-like structure. Several subsets of lasso peptide gene clusters feature a "split" B protein on separate open reading frames (B1 and B2), suggesting distinct functions for the B protein in lasso peptide biosynthesis...
October 18, 2016: Scientific Reports
Xiantao Shen, Chuixiu Huang, Sudhirkumar Shinde, Kishore Kumar Jagadeesan, Simon Ekström, Emelie Fritz, Börje Sellergren
This work describes the preparation and investigation of molecularly imprinted polymer (MIP) microgels (MGs) stabilized Pickering emulsions (PE) for their ability to catalyze the formation of disulfide bonds in peptides at the O/W interface. The MIP MGs were synthesized via precipitation polymerization and a programmed initiator change strategy. The MIP MGs were characterized using DLS analysis, SEM measurement and optical microscopy analysis. The dry and wet MIP MGs showed a hydrodynamic diameter of 100 nm and 280 nm, respectively...
October 17, 2016: ACS Applied Materials & Interfaces
Xinxin Gao, Karen Stanger, Harini Kaluarachchi, Till Maurer, Paulina Ciepla, Cecile Chalouni, Yvonne Franke, Rami N Hannoush
Cyclotides or cyclic cystine-knot peptides have emerged as a promising class of pharmacological ligands that modulate protein function. Interestingly, very few cyclotides have been shown to enter into cells. Yet, it remains unknown whether backbone cyclization is required for their cellular internalization. In this report, we studied the cellular behavior of EETI-II, a model acyclic cystine-knot peptide. Even though synthetic methods have been used to generate EETI-II, recombinant methods that allow efficient large scale biosynthesis of EETI-II have been lagging...
October 13, 2016: Scientific Reports
Andrew M White, David J Craik
Macrocyclic peptides are generally more resistant to proteolysis and often have higher potency than linear peptides and so they are excellent leads in drug design. Their study is significant because they offer potential as a new generation of drugs that are potent and specific, and thus might have fewer side effects than traditional small molecule drugs. Areas covered: This article covers macrocyclic drug leads based on nature-derived cyclic peptides as well as synthetic cyclic peptides and close derivatives...
October 10, 2016: Expert Opinion on Drug Discovery
Nina Bionda, Rudi Fasan
Many biologically active peptides found in nature exhibit a bicyclic structure wherein a head-to-tail cyclic backbone is further constrained by an intramolecular linkage connecting two side chains of the peptide. Accordingly, methods to access macrocyclic peptides sharing this overall topology could be of significant value toward the discovery of new functional entities and bioactive compounds. With this goal in mind, we recently developed a strategy for enabling the biosynthesis of thioether-bridged bicyclic peptides in living bacterial cells...
2017: Methods in Molecular Biology
Eliot L Osher, Ali Tavassoli
Cyclic peptides are an important class of molecules that are increasingly viewed as an ideal scaffold for inhibition of protein-protein interactions (PPI). Here we detail an approach that enables the intracellular synthesis of cyclic peptide libraries of around 10(8) members. The method utilizes split intein mediated circular ligation of peptides and proteins (SICLOPPS), taking advantage of split intein splicing to cyclize a library of peptide sequences. SICLOPPS allows the ring size, set residues and number of random residues within a library to be predetermined by the user...
2017: Methods in Molecular Biology
Ryan A Davis, Kevin Lau, Sven H Hausner, Julie L Sutcliffe
Solid-phase peptide synthesis, head-to-tail cyclization, and subsequent radiolabeling provided a reproducible, simple, rapid synthetic method to generate the cyclic peptide radiotracer cRGDyK([(18)F]FBA). Herein is reported the first on-resin cyclization and (18)F-radiolabeling of a cyclic peptide (cRGDyK) in an overall peptide synthesis yield of 88% (cRGDyK(NH2)) and subsequent radiolabeling yield of 14 ± 2% (decay corrected, n = 4). This approach is generally applicable to the development of an automated process for the synthesis of cyclic radiolabeled peptides for positron emission tomography (PET)...
September 21, 2016: Organic & Biomolecular Chemistry
Michael T Ringel, Gerald Draeger, Thomas Brueser
Pyoverdines are high-affinity siderophores produced by a broad range of pseudomonads to enhance growth under iron-deficiency. They are especially relevant for pathogenic and mutualistic strains that inhabit iron-limited environments. Pyoverdines are generated from non-ribosomally synthesized highly modified peptides. They all contain an aromatic chromophore that is formed in the periplasm by intramolecular cyclization steps. While the cytoplasmic peptide synthesis and side-chain modifications are well-characterized, the periplasmic maturation steps are far from understood...
October 4, 2016: Journal of Biological Chemistry
Alysha G Elliott, Bastian Franke, David A Armstrong, David J Craik, Joshua S Mylne, K Johan Rosengren
We recently isolated and described the evolutionary origin of a diverse class of small single-disulfide bonded peptides derived from Preproalbumin with SFTI-1 (PawS1) proteins in the seeds of flowering plants (Asteraceae). The founding member of the PawS derived peptide (PDP) family is the potent trypsin inhibitor SFTI-1 (sunflower trypsin inhibitor-1) from Helianthus annuus, the common sunflower. Here we provide additional structures and describe the structural diversity of this new class of small peptides, derived from solution NMR studies, in detail...
October 1, 2016: Amino Acids
Davide Carta, Nicola Salvarese, Nicolò Morellato, Feng Gao, Wiebke Sihver, Hans Jurgen Pietzsch, Barbara Biondi, Paolo Ruzza, Fiorenzo Refosco, Debora Carpanese, Antonio Rosato, Cristina Bolzati
The purpose of this study was to evaluate the effect of cyclization on the biological profile of a [(99m)Tc(N)(PNP3)]-labeled α-melanocyte stimulating hormone peptide analog. A lactam bridge-cyclized H-Cys-Ahx-βAla(3)-c[Lys(4)-Glu-His-D-Phe-Arg-Trp-Glu(10)]-Arg(11)-Pro-Val-NH2 (NAP-NS2) and the corresponding linear H-Cys-Ahx-βAla-Nle-Asp-His-D-Phe-Arg-Trp-Gly-NH2 (NAP-NS1) peptide were synthetized, characterized by ESI-MS spectroscopy and their melanocortin-1 receptor (MC1R) binding affinity was determined in B16/F10 melanoma cells...
August 31, 2016: Nuclear Medicine and Biology
Man Ying, Qing Shen, Changyou Zhan, Xiaoli Wei, Jie Gao, Cao Xie, Bingxin Yao, Weiyue Lu
Peptide ligands consisting of l-amino acids are subject to proteolysis in vivo. When modified on the surface of nanocarriers, those peptide ligands would readily degrade and the targeting efficacy is significantly attenuated. It has received increasing scrutiny to design stable peptide ligands for targeted drug delivery. Here, we present the design of a stable peptide ligand by the formation of a head-to-tail amide bond as an example. Even though the linear l-peptide A7R (termed (L)A7R) can bind specifically to vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1) that are overexpressed on glioma cells, neovasculature and glioma vasculogenic mimicry (VM), the tumor-homing capacity of (L)A7R is greatly impaired in vivo due to proteolysis (e...
September 29, 2016: Journal of Controlled Release: Official Journal of the Controlled Release Society
Olivier Van der Poorten, Astrid Knuhtsen, Daniel Sejer Pedersen, Steven Ballet, Dirk Tourwé
Constraining the conformation of flexible peptides is a proven strategy to increase potency, selectivity and metabolic stability. The focus has mostly been on constraining the backbone dihedral angles; however, the correct orientation of the amino acid side chains (Χ-space) which constitute the peptide pharmacophore is equally important. Control of Χ-space utilizes conformationally constrained amino acids which favor, disfavor or exclude the gauche (‒), the gauche (+) or the trans conformation. In this review we focus on cyclic aromatic amino acids in which the side chain is connected to the peptide backbone to provide control of Χ1- and Χ2-space...
October 3, 2016: Journal of Medicinal Chemistry
Grazyna Weltrowska, Thi M-D Nguyen, Nga N Chung, JodiAnne Wood, Xiaoyu Ma, Jason Guo, Brian C Wilkes, Yang Ge, André Laferrière, Terence J Coderre, Peter W Schiller
Head-to-tail cyclization of the μ opioid receptor (MOR) agonist [Dmt(1)]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2 (9; Dmt = 2',6'-dimethyltyrosine) resulted in a highly active, selective MOR antagonist, c[-d-Arg-Phe-Lys-Dmt-] (1) ("cyclodal"), with subnanomolar binding affinity. A docking study of cyclodal using the crystal structure of MOR in the inactive form showed a unique binding mode with the two basic residues of the ligand forming salt bridges with the Asp(127) and Glu(229) receptor residues. Cyclodal showed high plasma stability and was able to cross the blood-brain barrier to reverse morphine-induced, centrally mediated analgesia when given intravenously...
October 3, 2016: Journal of Medicinal Chemistry
Carolyn L Fisher, Ross J Resnick, Soumya De, Lucila A Acevedo, Kun Ping Lu, Frank C Schroeder, Linda K Nicholson
The cis/trans isomerization of X-Pro peptide bonds in proteins in some instances acts as a molecular switch in biological pathways. Our prior work suggests that the cis isomer of the phospho-Thr668-Pro669 motif, located in the cytoplasmic domain of the amyloid-β protein precursor (AβPP), is correlated with an increase in amyloidogenic processing of AβPP and production of amyloid-beta (Aβ), the neurotoxic peptide fragment in Alzheimer's disease (AD). We designed a 100% cis-locked cyclic dipeptide composed of cyclized phospho-Thr-Pro (pCDP) as a mimic for this putative pathological conformation, and three phosphate-blocked derivatives (pCDP-diBzl, pCDP-Bzl, and pCDP-diPOM)...
September 21, 2016: Journal of Alzheimer's Disease: JAD
James R Kintzing, Jennifer R Cochran
Inhibitor cystine-knots, also known as knottins, are a structural family of ultra-stable peptides with diverse functions. Knottins and related backbone-cyclized peptides called cyclotides contain three disulfide bonds connected in a particular arrangement that endows these peptides with high thermal, proteolytic, and chemical stability. Knottins have gained interest as candidates for non-invasive molecular imaging and for drug development as they can possess the pharmacological properties of small molecules and the target affinity and selectively of protein biologics...
September 16, 2016: Current Opinion in Chemical Biology
Cillian Byrne, Morkos A Henen, Mathilde Belnou, François-Xavier Cantrelle, Amina Kamah, Haoling Qi, Julien Giustiniani, Béatrice Chambraud, Etienne-Emile Baulieu, Guy Lippens, Isabelle Landrieu, Yves Jacquot
The immunophilin FKBP52 interacts with nuclear steroid hormone receptors. Studying the crystal structure of human estrogen receptor α (hERα) and using nuclear magnetic resonance, we show here that the short V(364)PGF(367) sequence, which is located within its ligand-binding domain and adopts a type II β-turn conformation in the protein, binds the peptidyl-prolyl isomerase (PPIase or rotamase) FK1 domain of FKBP52. Interestingly, this turn motif displays strong similarities with the FKBP52 FK1 domain-binding moiety of macrolide immunomodulators such as rapamycin and GPI-1046, an immunophilin ligand with neuroprotective characteristics...
September 27, 2016: Biochemistry
Chao Zhang, Cheng Yang, Tongyu Zhu
Erythropoietin (EPO), recognized early as a tissue protective agent, can trigger anti-inflammatory and anti-apoptotic processes to delimit injury and promote repair by binding tissue-protective receptor (TPR). However, only at a high dosage can EPO exert tissue protective effect, which may elicit severe side-effects at the meantime. Helix B surface peptide (HBSP), a 11-amnio acid sequence derived from the non-erythropoietic helix B of EPO, not only shows higher affinity to TPR but also plays a more specific and powerful role in tissue protection without erythropoietic side-effects...
September 9, 2016: Current Protein & Peptide Science
John Rafferty, Hema Nagaraj, Alice P McCloskey, Rawan Huwaitat, Simon Porter, Alyaa Albadr, Garry Laverty
Peptides are receiving increasing interest as clinical therapeutics. These highly tunable molecules can be tailored to achieve desirable biocompatibility and biodegradability with simultaneously selective and potent therapeutic effects. Despite challenges regarding up-scaling and licensing of peptide products, their vast clinical potential is reflected in the 60 plus peptide-based therapeutics already on the market, and the further 500 derivatives currently in developmental stages. Peptides are proving effective for a multitude of disease states including: type 2 diabetes (controlled using the licensed glucagon-like peptide-1 receptor liraglutide); irritable bowel syndrome managed with linaclotide (currently at approval stages); acromegaly (treated with octapeptide somostatin analogues lanreotide and octreotide); selective or broad spectrum microbicidal agents such as the Gram-positive selective PTP-7 and antifungal heliomicin; anticancer agents including goserelin used as either adjuvant or monotherapy for prostate and breast cancer, and the first marketed peptide derived vaccine against prostate cancer, sipuleucel-T...
September 9, 2016: Current Medicinal Chemistry
Sedigheh Rezaeianpour, Atefeh Hajiagha Bozorgi, Abolghasem Moghimi, Ameneh Almasi, Saeed Balalaie, Sorour Ramezanpour, Sanaz Nasoohi, Seyed Mohammad Mazidi, Parham Geramifar, Ahmad Bitarafan-Rajabi, Soraya Shahhosseini
PURPOSE: Many patients worldwide suffer from cardiovascular diseases for which an underlying factor is thrombosis. Devising a molecular imaging technique for early detection of thrombosis in a clinical setting is highly recommended. Because fibrin is a major constituent of clots and is present in all types of thrombi but absent in circulation, it is a highly specific and sensitive target for molecular imaging of thrombi. It is assumed that cyclization of peptides will improve the receptor binding affinity and stability of the peptide...
September 8, 2016: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
Gaurav Bhardwaj, Vikram Khipple Mulligan, Christopher D Bahl, Jason M Gilmore, Peta J Harvey, Olivier Cheneval, Garry W Buchko, Surya V S R K Pulavarti, Quentin Kaas, Alexander Eletsky, Po-Ssu Huang, William A Johnsen, Per Jr Greisen, Gabriel J Rocklin, Yifan Song, Thomas W Linsky, Andrew Watkins, Stephen A Rettie, Xianzhong Xu, Lauren P Carter, Richard Bonneau, James M Olson, Evangelos Coutsias, Colin E Correnti, Thomas Szyperski, David J Craik, David Baker
Naturally occurring, pharmacologically active peptides constrained with covalent crosslinks generally have shapes that have evolved to fit precisely into binding pockets on their targets. Such peptides can have excellent pharmaceutical properties, combining the stability and tissue penetration of small-molecule drugs with the specificity of much larger protein therapeutics. The ability to design constrained peptides with precisely specified tertiary structures would enable the design of shape-complementary inhibitors of arbitrary targets...
September 14, 2016: Nature
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