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Constrained peptide

Dorian Migoń, Damian Neubauer, Wojciech Kamysz
Antimicrobial peptides are promising candidates for anti-infective pharmaceuticals. Unfortunately, because of their low proteolytic and chemical stability, their usage is generally narrowed down to topical formulations. Until now, numerous approaches to increase peptide stability have been proposed. One of them, peptide hydrocarbon stapling, a modification based on stabilizing peptide secondary structure with a side-chain covalent hydrocarbon bridge, have been successfully applied to many peptides. Moreover, constraining secondary structure of peptides have also been proven to increase their biological activity...
January 12, 2018: Protein Journal
Edit Mesterházy, Colette Lebrun, Attila Jancsó, Pascale Delangle
Peptide design is an efficient strategy to create relevant models of natural metal binding sites found in proteins. The two short tetrapeptides Ac-Cys-dPro-Pro-Cys-NH2 (CdPPC) and Ac-Cys-Pro-Gly-Cys-NH2 (CPGC) were synthesized and studied as mimics of Cu(I) binding sites involved in Cu homeostasis. Both sequences contain β turn inducing motifs to rigidify the peptide backbone structure and thereby preorganize the metal-binding side chains. The more constrained structure of the peptide CdPPC with respect to CPGC was evidenced by the measurements of the temperature coefficients of the amide protons by 1H NMR, which suggest a solvent-shielded intramolecular hydrogen bond in CdPPC, and no H-bond in CPGC...
January 12, 2018: Inorganic Chemistry
Xiyuan Wu, Zixuan Liu, Xiaohui Ding, Danwei Yu, Huamian Wei, Bo Qin, Yuanmei Zhu, Huihui Chong, Sheng Cui, Yuxian He
SC29EK is an electronically constrained α-helical peptide HIV-1 fusion inhibitor highly effective against both wild-type and enfuvirtide (T20)-resistant viruses. In this study, we focused on investigating the mechanism of HIV-1 resistance to SC29EK by two approaches. First, SC29EK-escaping HIV-1 variants were selected and characterized. Three mutant viruses, which possessed two (E43K/E49A) or three (Q39R/N43K/N126K, N43K/E49A/N126K) amino acid substitutions in the N- and C-terminal repeat regions of gp41 were identified as conferring high resistance to SC29EK and cross-resistance to the first-generation (T20, C34) and newly-designed (sifuvirtide, MT-SC29EK, 2P23) fusion inhibitors...
January 10, 2018: Journal of Virology
Govind S Bhosle, Shalmali Kharche, Santosh Kumar, Durba Sengupta, Souvik Maiti, Moneesha Fernandes
We report a hundred-fold increase in binding affinity of the Tat(48-57) peptide to HIV-1 TAR RNA by replacing R52, an essential and critical residue for Tat's specific binding, by (2S,4S)-4-guanidinoproline. The resulting αTat1M peptide is a far superior binder than γTat1M, a peptide containing another conformationally constrained arginine mimic, (2S,4S)-4-amino-N-(3-guanidinopropyl)-proline, or even the control Tat (CtrlTat) itself. Our observations are supported by CD, ITC, gel electrophoresis and UV spectroscopy studies...
January 4, 2018: ChemMedChem
Anjali Jha, Mothukuri Ganesh Kumar, Hosahudya N Gopi, Kishore M Paknikar
Designing peptide based drugs to target the β-sheet rich toxic intermediates during the aggregation of amyloid-β 1-42 (Aβ1-42) has been a major challenge. In general, β-sheet breaker peptides (BSBPs) are designed to complement the enthalpic interactions with the aggregating protein and entropic effects are usually ignored. Here, we have developed a conformationally constrained cyclic BSBP by the use of an unnatural amino acid and a disulfide bond. We show that our peptide strongly inhibits the aggregation of Aβ1-42 in a concentration-dependent manner...
December 28, 2017: Langmuir: the ACS Journal of Surfaces and Colloids
Aldo Franco, Sanaz Dovell, Carolina Moller, Meghan Grandal, Evan Clark, Frank Marí
The mini-M conotoxins are peptidic scaffolds found in the venom of cones snails. These scaffolds are tightly folded structures held together by three disulfide bonds with a CC-C-C-CC arrangement (conotoxin framework III) and belong to the M Superfamily of conotoxins. Here we describe twenty-five mini-M conotoxins from the venom of Conus regius, a Western Atlantic worm-hunting cone snail species using transcriptomic and peptidomic analyses. These C. regius conotoxins belong to three different subtypes: M1, M2, and M3...
December 28, 2017: FEBS Journal
Wei-Jie Fang, Thomas F Murray, Jane V Aldrich
Kappa (κ) opioid receptor selective antagonists are useful pharmacological tools in studying κ opioid receptors and have potential to be used as therapeutic agents for the treatment of a variety of diseases including mood disorders and drug addiction. Arodyn (Ac[Phe1-3,Arg4,d-Ala8]Dyn A-(1-11)NH2) is a linear acetylated dynorphin A (Dyn A) analog that is a potent and selective κ opioid receptor antagonist (Bennett et al. J Med Chem 2002;45:5617-5619) and prevents stress-induced reinstatement of cocaine-seeking behavior following central administration (Carey et al...
November 21, 2017: Bioorganic & Medicinal Chemistry
S A Bode, D W P M Löwik
In this review we provide an overview of recent developments in the field of cell penetrating peptides (CPPs) on research that aims to achieve better control over their transduction properties - one of the big challenges - by means of restraining them. Three different constraining strategies are presented: triggerable activation, backbone rigidification and macrocyclization. Each of these methods have their opportunities in gaining control over CPP activity and selectivity.
December 2017: Drug Discovery Today. Technologies
Serge Zaretsky, Andrei K Yudin
Constrained peptides pose tremendous value in drug discovery. For example, owing to their large surface areas, they offer novel ways at inhibiting protein-protein interactions. As this field has grown, it has become desirable to introduce non-peptidic functionality into these rings to enable differentiated structure activity relationships and improved pharmacokinetic properties. Recent advances in the synthesis of cyclic pseudopeptides include macrocyclization through cysteine alkylation, multicomponent reactions, decarboxylative couplings, and novel stapling chemistry...
December 2017: Drug Discovery Today. Technologies
Jan H van Maarseveen, Peter Timmerman
No abstract text is available yet for this article.
December 2017: Drug Discovery Today. Technologies
Julien Giribaldi, Sébastien Dutertre
The vast diversity of neuronal nicotinic acetylcholine subunits expressed in the central and peripheral nervous systems, as well as in non-neuronal tissues, constitutes a formidable challenge for researchers and clinicians to decipher the role of particular subtypes, including complex subunit associations, in physiological and pathophysiological functions. Many natural products target the nAChRs, but there is no richer source of nicotinic ligands than the venom of predatory gastropods known as cone snails. Indeed, every single species of cone snail was shown to produce at least one type of such α-conotoxins...
November 30, 2017: Neuroscience Letters
Jonathon O'Brien, Jeremy D O'Connell, Joao A Paulo, Sanjukta Thakurta, Christopher M Rose, Michael P Weekes, Edward L Huttlin, Steven P Gygi
Mass spectrometry (MS) has become an accessible tool for whole proteome quantitation with the ability to characterize protein expression across thousands of proteins within a single experiment. A subset of MS quantification methods (e.g., SILAC and label-free) monitor the relative intensity of intact peptides, where thousands of measurements can be made from a single mass spectrum. An alternative approach, isobaric labeling, enables precise quantification of multiple samples simultaneously through unique and sample specific mass reporter ions...
December 1, 2017: Journal of Proteome Research
Sang Eun Ryu, Tammy Shim, Ju-Yeon Yi, So Yeun Kim, Sun Hwa Park, Sung Won Kim, Gabriele V Ronnett, Cheil Moon
Mammalian genomes are well established, and highly conserved regions within odorant receptors that are unique from other G-protein coupled receptors have been identified. Numerous functional studies have focused on specific conserved amino acids motifs, however, not all conserved motifs have been sufficiently characterized. Here, we identified a highly conserved 18 amino acid sequence motif within transmembrane domain seven (CAS-TM7) which was identified by aligning odorant receptor sequences. Next, we investigated the expression pattern and distribution of this conserved amino acid motif among a broad range of odorant receptors...
November 23, 2017: Molecules and Cells
Olivier Van der Poorten, Robin Van Den Hauwe, Emilie Eiselt, Cecilia Betti, Karel Guillemyn, Nga N Chung, François Hallé, Frédéric Bihel, Peter W Schiller, Dirk Tourwé, Philippe Sarret, Louis Gendron, Steven Ballet
Herein, the synthesis of novel conformationally constrained amino acids, 4-amino-8-bromo-2-benzazepin-3-one (8-Br-Aba), 3-amino-3,4-dihydroquinolin-2-one, and regioisomeric 4-amino-naphthoazepinones (1- and 2-Ana), is described. Introduction of these constricted scaffolds into the N-terminal tetrapeptide of dermorphin (i.e., H-Tyr-d-Ala-Phe-Gly-NH2) induced significant shifts in binding affinity, selectivity, and in vitro activity at the μ- and δ-opioid receptors (MOP and DOP, respectively). A reported constrained μ-/δ-opioid lead tetrapeptide H-Dmt-d-Arg-Aba-Gly-NH2 was modified through application of various constrained building blocks to identify optimal spatial orientations in view of activity at the opioid receptors...
November 9, 2017: ACS Medicinal Chemistry Letters
Grégory Chaume, Julien Simon, Nathalie Lensen, Julien Pytkowicz, Thierry Brigaud, Emeric Miclet
The design of constrained peptides is of prime importance in the development of bioactive compounds and for applications in supramolecular chemistry. Due to its nature, the peptide bond undergoes a spontaneous cis-trans isomerism and the cis isomers are much more difficult to stabilize than the trans forms. By using oxazolidine-based pseudoprolines (ΨPro) substituted by a trifluoromethyl group, we show that the cis peptide bond can be readily switched from 0% to 100% in Xaa-ΨPro dipeptides. Our results prove that changing the configuration of the Cα in Xaa or in ΨPro is sufficient to invert the cis:trans populations while changing the nature of the Xaa side chain finely tuned the conformers ratio...
November 15, 2017: Journal of Organic Chemistry
Enrico F Semeraro, Juliette M Devos, Lionel Porcar, V Trevor Forsyth, Theyencheri Narayanan
The flagellated Gram-negative bacterium Escherichia coli is one of the most studied microorganisms. Despite extensive studies as a model prokaryotic cell, the ultrastructure of the cell envelope at the nanometre scale has not been fully elucidated. Here, a detailed structural analysis of the bacterium using a combination of small-angle X-ray and neutron scattering (SAXS and SANS, respectively) and ultra-SAXS (USAXS) methods is presented. A multiscale structural model has been derived by incorporating well established concepts in soft-matter science such as a core-shell colloid for the cell body, a multilayer membrane for the cell wall and self-avoiding polymer chains for the flagella...
November 1, 2017: IUCrJ
Colleen A Flanagan, Ashmeetha Manilall
Gonadotropin-releasing hormone (GnRH) regulates reproduction. The human GnRH receptor lacks a cytoplasmic carboxy-terminal tail but has amino acid sequence motifs characteristic of rhodopsin-like, class A, G protein-coupled receptors (GPCRs). This review will consider how recent descriptions of X-ray crystallographic structures of GPCRs in inactive and active conformations may contribute to understanding GnRH receptor structure, mechanism of activation and ligand binding. The structures confirmed that ligands bind to variable extracellular surfaces, whereas the seven membrane-spanning α-helices convey the activation signal to the cytoplasmic receptor surface, which binds and activates heterotrimeric G proteins...
2017: Frontiers in Endocrinology
Meng-Chen Lu, Qiong Jiao, Tian Liu, Shi-Jie Tan, Hai-Shan Zhou, Qi-Dong You, Zheng-Yu Jiang
Directly disrupting Keap1-Nrf2 protein-protein interaction (PPI) has emerged as a novel way to activate Nrf2. Peptide Keap1-Nrf2 PPI inhibitors have been reported with high Keap1 binding affinity. However, these peptide inhibitors show weak activity in cells. In this study, the head-to-tail cyclic strategy was applied in the development of peptide inhibitors. The privileged residue sequence with minimal acidic residues was used as the template for the cyclic peptide, and the appropriate conjugation method was designed based on the peptide-Keap1 binding mode...
October 19, 2017: European Journal of Medicinal Chemistry
Salvador Guardiola, Jesús Seco, Monica Varese, Mireia Díaz-Lobo, Jesus Garcia, Meritxell Teixido, Laura Nevola, Ernest Giralt
In cancer, proliferation of malignant cells is driven by overactivation of growth signaling mechanisms, such as the EGF-EGFR pathway. Despite its therapeutic relevance, this extracellular protein-protein interaction (PPI) has remained elusive to inhibition by synthetic molecules, mostly due to its large size and lack of binding pockets and cavities. Designed peptides, featuring cyclic motifs and other structural constraints, have the potential to modulate such challenging PPIs. Here we present the structure-based design of a series of bicyclic constrained peptides that mimic an interface domain of EGFR and inhibit the EGF-EGFR interaction by targeting the smaller partner (EGF)...
November 6, 2017: Chembiochem: a European Journal of Chemical Biology
Yang Zhou, Saghar Mowlazadeh Haghighi, Ioanna Zoi, Jonathon R Sawyer, Victor J Hruby, Minying Cai
Melanoma is a lethal form of skin cancer. Skin pigmentation, which is regulated by the melanocortin 1 receptor (MC1R), is an effective protection against melanoma. However, the endogenous MC1R agonists lack selectivity for the MC1R and thus can have side effects. The use of noncanonical amino acids in previous MC1R ligand development raises safety concerns. Here we report the development of the first potent and selective hMC1R agonist with only canonical amino acids. Using γ-MSH as a template, we developed a peptide, [Leu(3), Leu(7), Phe(8)]-γ-MSH-NH2 (compound 5), which is 16-fold selective for the hMC1R (EC50 = 4...
November 13, 2017: Journal of Medicinal Chemistry
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