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Constrained peptide

Mathias Hallberg, Anja Sandström
Substance P (SP) is associated with pain and inflammatory processes and is released from terminals of specific sensory nerves. This undecapeptide that mediates its effects through the neurokinin type 1 (NK1) receptor, is rapidly degraded in vivo to smaller fragments. The heptapeptide SP(1-7) with a hitherto unknown receptor, is a major bioactive fragment and displays often opposite actions to those induced by SP. Hence, SP(1-7) elicits anti-nociceptive and anti-hyperalgesic effects. These observations have attracted a substantial interest and in this mini-review the efforts to transform the heptapeptide SP(1-7) into more drug-like small-molecule SP(1-7) peptidomimetics as a potential new class of analgesics are summarized...
May 8, 2018: Current Protein & Peptide Science
Lorenzo Sernissi, Luciano Ricci, Dina Scarpi, Francesca Bianchini, Daniela Arosio, Alessandro Contini, Ernesto G Occhiato
A stereodivergent strategy was devised to obtain enantiopure cis and trans 5-aminopipecolic acids (5-APAs) in suitably protected forms to be employed in peptide synthesis as conformationally constrained α- and δ-amino acids. The cis isomer was used as a δ-amino acid to construct a cyclic RGD-containing peptidomimetic, the ability of which to compete with biotinylated vitronectin for binding with the isolated αVβ3 integrin was measured (IC50 = 4.2 ± 0.9 nM). A complete 1H NMR and computational conformational analysis was performed to elucidate the reasons for the high affinity of this cyclic peptidomimetic in comparison with cilengitide...
April 20, 2018: Organic & Biomolecular Chemistry
Naomi S Robertson, David R Spring
Protein⁻protein interactions (PPIs) are tremendously important for the function of many biological processes. However, because of the structure of many protein⁻protein interfaces (flat, featureless and relatively large), they have largely been overlooked as potential drug targets. In this review, we highlight the current tools used to study the molecular recognition of PPIs through the use of different peptidomimetics, from small molecules and scaffolds to peptides. Then, we focus on constrained peptides, and in particular, ways to constrain α-helices through stapling using both one- and two-component techniques...
April 19, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Conan K Wang, David J Craik
Bioactive peptides have potential as drug leads, but turning them into drugs is a challenge because of their typically poor metabolic stability. Molecular grafting is one approach to stabilizing and constraining peptides and involves melding a bioactive peptide sequence onto a suitable molecular scaffold. This method has the benefit of improving the stability of the bioactive peptide lead and potentially expanding its functionality. Here we step through the molecular grafting process and describe its successes and limitations...
May 2018: Nature Chemical Biology
Marina V Rodnina
This review summarizes our current understanding of translation in prokaryotes, focusing on the mechanistic and structural aspects of each phase of translation: initiation, elongation, termination, and ribosome recycling. The assembly of the initiation complex provides multiple checkpoints for messenger RNA (mRNA) and start-site selection. Correct codon-anticodon interaction during the decoding phase of elongation results in major conformational changes of the small ribosomal subunit and shapes the reaction pathway of guanosine triphosphate (GTP) hydrolysis...
April 16, 2018: Cold Spring Harbor Perspectives in Biology
Hader E Elashal, Ryan D Cohen, Heidi E Elashal, Chuhan Zong, A James Link, Monika Raj
A broadly-applicable chemical cleavage methodology to facilitate MS/MS sequencing was developed for macrocyclic and lasso peptides, which holds promise as exciting new therapeutics. Existing methods such as Edman degradation, CNBr cleavage, and enzymatic digestion are either limited in scope or completely fail in cleavage of constrained non-ribosomal peptides. Importantly, the new method was utilized for synthesizing a unique peptide-based rotaxane (both cycle and thread) from the lasso peptide, benenodin-1 ΔC5...
April 12, 2018: Angewandte Chemie
Yiwu Zheng, Xiaoting Meng, Yaqi Wu, Yibing Zhao, Chuanliu Wu
Disulfide-rich peptides are interesting scaffolds for drug design and discovery. However, peptide scaffolds constrained by disulfide bonds, either naturally occurring or computationally designed, have been suffering from the elusive (oxidative) folding behavior complying with Anfinsen's dogma, which strongly restricts their applicability in bioactive peptide design and discovery; because when primary peptide sequences are extensively manipulated, their disulfide connectivities might become scrambled. Here we present the design of cysteine/penicillamine (C/Pen)-mixed peptide frameworks that are capable of folding into specific regioisomers without dependence on primary amino acid sequences...
January 21, 2018: Chemical Science
Patrick J Salveson, Sepehr Haerianardakani, Alexander Thuy-Boun, Adam G Kreutzer, James S Nowick
A key challenge in studying the biological and biophysical properties of amyloid-forming peptides is that they assemble to form heterogenous mixtures of soluble oligomers and insoluble fibrils. Photolabile protecting groups have emerged as tools to control the properties of biomolecules with light. Blocking intermolecular hydrogen bonds that stabilize amyloid oligomers provides a general strategy to control the biological and biophysical properties of amyloid-forming peptides. This paper describes the design, synthesis, and characterization of macrocyclic β-hairpin peptides that are derived from amyloidogenic peptides and contain the N-2-nitrobenzyl photolabile protecting group...
April 8, 2018: Journal of the American Chemical Society
Mirao Zha, Ping Lin, Hongwei Yao, Yibing Zhao, Chuanliu Wu
Bicyclic peptides have been attractive scaffolds for developing high affinity reagents for biomacromolecules. Here we report a general phage-screening strategy for the development of bicyclic peptide ligands constrained with isomerically-forbidden disulfide bridges without elaborate chemical modifications and recourses to genetic code reprogramming.
April 5, 2018: Chemical Communications: Chem Comm
Judith Silverman, Ebrima Gibbs, Xubiao Peng, Kris Martens, Claudia Balducci, Jing Wang, Masoud Yousefi, Catherine M Cowan, Guillaume Lamour, Sarah Louadi, Yuxin Ban, Jerome Robert, Sophie Stukas, Gianluigi Forloni, Ging-Yuek R Hsiung, Steven S Plotkin, Cheryl L Wellington, Neil R Cashman
Oligomers of Amyloid-β (AβO) are deemed key in synaptotoxicity and amyloid seeding of Alzheimer's disease (AD). However, the heterogeneous and dynamic nature of AβO, and inadequate markers for AβO subtypes, have stymied effective AβO identification and therapeutic targeting in vivo. We identified an AβO-subclass epitope defined by differential solvent orientation of the lysine 28 sidechain in a constrained loop of serine-asparagine-lysine (cSNK), rarely displayed in molecular dynamics simulations of monomer and fibril ensembles...
April 4, 2018: ACS Chemical Neuroscience
Stefan Lenz, Philip Horx, Armin Geyer
Maleimide-thiol coupling is a popular bioconjugation strategy, but little is known about the stereoselectivity and the stereodynamics of the succinimide thioether formed in a biopolymer environment. We used thiol 1,4-addition for the macrocyclisation of 5 designed pentapeptides with the ringsize of hexapeptides because they incorporate the succinimide thioether (4-8). Both succinimide diastereomers are observed in the constrained macrocyclic rings in each case. In spite of the low diastereoselectivity of the macrocyclisation reaction, there is a significant influence of the amino acid environment on the epimerization rate of the succinimide...
March 27, 2018: Journal of Peptide Science: An Official Publication of the European Peptide Society
Salvador Eugenio C Caoili
The contemporary Anthropocene is characterized by rapidly evolving complex global challenges to planetary health vis-a-vis sustainable development, yet innovation is constrained under the prevailing precautionary regime that regulates technological change. Small-molecule xenobiotic drugs are amenable to efficient large-scale industrial synthesis; but their pharmacokinetics, pharmacodynamics, interactions and ultimate ecological impact are difficult to predict, raising concerns over initial testing and environmental contamination...
March 2018: Future Science OA
Yuan Tian, Xiangze Zeng, Jingxu Li, Yanhong Jiang, Hui Zhao, Dongyuan Wang, Xuhui Huang, Zigang Li
Due to their enhanced stability and cell permeability, cyclic cell-penetrating peptides have been widely used as delivery vectors for transporting cell-impermeable cargos into cells. In this study, we synthesized a panel of conformationally constrained peptides with either α-helix or β-hairpin conformations. We tuned the amphiphilicity of these constrained peptides with different distributions of charged or hydrophobic residues and compared their cellular uptake efficiencies in different cell lines. We found that the amphipathicity of these conformationally constrained peptides correlates well with their cellular uptake efficiency...
November 1, 2017: Chemical Science
Joana Couto, Miray Tonk, Joana Ferrolho, Sandra Antunes, Andreas Vilcinskas, José de la Fuente, Ana Domingos, Alejandro Cabezas-Cruz
Malaria is a mosquito-borne disease affecting millions of people mainly in Sub-Saharan Africa, Asia and some South American countries. Drug resistance to first-line antimalarial drugs (e.g. chloroquine, sulfadoxine-pyrimethamine and artemisinin) is a major constrain in malaria control. Antimicrobial peptides (AMPs) have shown promising results in controlling Plasmodium spp. parasitemia in in vitro and in vivo models of infection. Defensins are AMPs that act primarily by disrupting the integrity of cell membranes of invasive microbes...
March 15, 2018: Ticks and Tick-borne Diseases
Takeshi Yamada, Miu Yagita, Yutaka Kobayashi, Goh Sennari, Hiroyuki Shimamura, Hidehito Matsui, Yuki Horimatsu, Hideaki Hanaki, Tomoyasu Hirose, Satoshi Omura, Toshiaki Sunazuka
Total synthesis of bottromycin A2 can be accomplished through a diastereoselective Mannich reaction of a chiral sulfinamide, mercury-mediated intermolecular amidination, and cyclization of a constrained tetracyclic peptide. Exploitation of this process allowed the synthesis of several novel bottromycin analogs. The antimicrobial activity of these analogs was evaluated in vitro against Gram-positive bacteria, such as methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant enterococci (VRE)...
March 21, 2018: Journal of Organic Chemistry
Karl N Blodgett, Xiao Zhu, Patrick S Walsh, Dewei Sun, Jaeyeon Lee, Soo Hyuk Choi, Timothy S Zwier
The folding propensities of a capped, cyclically constrained, mixed <i>α</i>/<i>β</i>-diastereomer pair, (<i>SRSS</i>) Ac-Ala-<i>β</I><sub>ACHC</sub>-Ala-NHBn (hereafter <i>RS</i>) and (<i>SSRS</i>) Ac-Ala-<i>β</I><sub>ACHC</sub>-Ala-NHBn (<i>SR</i>), have been studied in a molecular beam using single-conformation spectroscopic techniques. These <i>α</i>/<i>β</i>-tripeptides contain a cyclohexane ring across each C<sub><i>α</i></sub>-C<sub><i>β</i></sub> bond, at which positions their stereochemistries differ...
March 20, 2018: Journal of Physical Chemistry. A
Joseph M Rogers, Sunbum Kwon, Simon J Dawson, Pradeep K Mandal, Hiroaki Suga, Ivan Huc
Translation, the mRNA-templated synthesis of peptides by the ribosome, can be manipulated to incorporate variants of the 20 cognate amino acids. Such approaches for expanding the range of chemical entities that can be produced by the ribosome may accelerate the discovery of molecules that can perform functions for which poorly folded, short peptidic sequences are ill suited. Here, we show that the ribosome tolerates some artificial helical aromatic oligomers, so-called foldamers. Using a flexible tRNA-acylation ribozyme-flexizyme-foldamers were attached to tRNA, and the resulting acylated tRNAs were delivered to the ribosome to initiate the synthesis of non-cyclic and cyclic foldamer-peptide hybrid molecules...
March 19, 2018: Nature Chemistry
Chayanid Ongpipattanakul, Satish Nair
Circular peptides have long been sought after as scaffolds for drug design as they demonstrate protein-like properties in the context of small, constrained peptides. Traditional routes towards the production of cyclic peptides rely on synthesis or semi-synthetic methods, which restrict their use as platforms for the production of large, structurally diverse chemical libraries. Here, we discuss the biosynthetic routes towards the N-C macrocyclization of linear peptide precursors, specifically, those transformations that are catalyzed by peptidases...
March 19, 2018: Biochemistry
Richard J Steel, Maria A O'Connell, Mark Searcey
The Nrf2/Keap1 interaction is a target in the development of new therapeutic agents, where inhibition of the interaction activates Nrf2 and leads to the generation of downstream anti-inflammatory effects. Peptides that mimic the β-turn in the Keap1 active site and are constrained by a disulfide bridge have high affinity for Keap1 but no intracellular activity. The introduction of a perfluoroalkyl-bridging group to constrain the peptides, coupled with a glutamic acid to proline replacement leads to a new peptide with a Ki of 6...
March 3, 2018: Bioorganic & Medicinal Chemistry Letters
Eileen J Kennedy
No abstract text is available yet for this article.
March 15, 2018: Bioorganic & Medicinal Chemistry
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