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| Open AccessIn vitro selection of macrocyclic peptide inhibitors containing cyclic γ2,4-amino acids targeting the SARS-CoV-2 main protease
In vitro screening of a ribosomally synthesized macrocyclic peptide library containing cyclic γ2,4-amino acids (cγAA) afforded the discovery of potent inhibitors of the SARS-CoV-2 main protease (Mpro). A co-crystal structure revealed the contribution of this cγAA to Mpro binding and the proteolytic stability of these macrocycles.
- Takashi Miura
- , Tika R. Malla
- & Hiroaki Suga
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Article
| Open AccessUnusual peptide-binding proteins guide pyrroloindoline alkaloid formation in crocagin biosynthesis
The alkaloids crocagins are derived from a ribosomal peptide through a series of enzymatic post-translational modifications. A combination of biochemistry and structural biology techniques has now been used to elucidate this biosynthetic pathway, propose a mechanism for the formation of the tetracyclic core structure and enable genome mining for related natural products.
- Sebastian Adam
- , Dazhong Zheng
- & Jesko Koehnke
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Article |
Protein nanopore reveals the renin–angiotensin system crosstalk with single-amino-acid resolution
A nanopore framework has been developed to reveal the crosstalk effect on the renin–angiotensin system. By reading the single-amino-acid differences in angiotensin peptides with high accuracy and high efficiency, the selective inhibition of angiotensin-converting enzyme by angiotensin-converting enzyme 2 was revealed. This activity was shown to be suppressed by the spike protein of SARS-CoV-2.
- Jie Jiang
- , Meng-Yin Li
- & Yi-Tao Long
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News & Views |
Cellular decoding for non-natural peptides
Ribosomes cannot synthesize peptides using hydroxy acids to replace canonical amino acids as no codons encode hydroxy acid building blocks. Now, this challenge has been addressed by rewriting the genetic code, enabling the direct cellular biosynthesis of non-natural depsipeptides containing non-canonical amino acids.
- Jian Li
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Article
| Open AccessGenetically programmed cell-based synthesis of non-natural peptide and depsipeptide macrocycles
Macrocyclic peptides can be genetically encoded and synthesized in cells; however, the programmable diversity is limited. Now, macrocycles containing two non-canonical amino acids have been genetically encoded and synthesized in codon-reassigned Syn61Δ3 cells. Incorporating diverse hydroxy acids in Syn61Δ3 cells enables the synthesis of non-natural depsipeptides containing either one or two ester bonds.
- Martin Spinck
- , Carlos Piedrafita
- & Jason W. Chin
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Article |
Post-translational backbone-acyl shift yields natural product-like peptides bearing hydroxyhydrocarbon units
Despite recent advances in engineering of in vitro translation systems, direct ribosomal incorporation of hydroxyhydrocarbon moieties—which can endow peptides with unique biochemical/folding properties—remains challenging. Now, incorporation of translation-compatible azide/hydroxy acids and their post-translational tandem backbone-acyl shifts have enabled in vitro ribosomal synthesis of peptides containing various hydroxyhydrocarbon units.
- Tomohiro Kuroda
- , Yichao Huang
- & Hiroaki Suga
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Article |
Machine learning overcomes human bias in the discovery of self-assembling peptides
Peptide design remains a challenge owing to the large library of amino acids. Rational design approaches, although successful, result in a peptide design bias. Now it has been shown that AI techniques can be used to overcome such bias and discover unusual peptides as efficiently as humans.
- Rohit Batra
- , Troy D. Loeffler
- & Subramanian K. R. S. Sankaranarayanan
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Article |
Synthesis and single-molecule imaging reveal stereospecific enhancement of binding kinetics by the antitumour eEF1A antagonist SR-A3
The total synthesis and complete stereochemical assignment of the cyclic peptide natural product SR-A3—which has potential as a cancer therapeutic—has now been reported. Single-molecule biophysical and cellular experiments reveal a crucial, stereospecific role for a side-chain hydroxyl in SR-A3, which confers enhanced target residence time and efficacy in a mouse tumour model.
- Hao-Yuan Wang
- , Haojun Yang
- & Jack Taunton
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Article |
Biosynthesis and characterization of fuscimiditide, an aspartimidylated graspetide
The biosynthesis of fuscimiditide, a ribosomally synthesized post-translationally modified peptide, has now been reported. Heterologous expression and analysis of fuscimiditide showed it contained two side-chain–side-chain ester linkages and an aspartimide in its backbone. The aspartimide moiety is unexpectedly stable, suggesting this structure is the intended natural product.
- Hader E. Elashal
- , Joseph D. Koos
- & A. James Link
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Article |
Conformational and functional changes of the native neuropeptide somatostatin occur in the presence of copper and amyloid-β
Metal-free amyloid-β (Aβ) and metal-bound Aβ (metal–Aβ) are found in the brain of patients with Alzheimer’s disease. Now, it has been shown that the conformation of a native neuropeptide, somatostatin, is changed in the presence of copper ions, Aβ and metal–Aβ. The conformational change results in a loss of function of somatostatin as a neurotransmitter and a gain of function as a modulator against metal–Aβ.
- Jiyeon Han
- , Jiwon Yoon
- & Mi Hee Lim
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Article |
Phase-separating peptides for direct cytosolic delivery and redox-activated release of macromolecular therapeutics
Coacervate microdroplets formed from pH- and redox-responsive peptides and self-assembled by liquid–liquid phase separation have been shown to quickly recruit macromolecular therapeutics—such as peptides, large proteins and mRNAs—and directly enter the cytosol of cells via a non-endocytic pathway. The subsequent release of therapeutic cargo is mediated by endogenic glutathione.
- Yue Sun
- , Sze Yi Lau
- & Ali Miserez
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Article |
A short peptide synthon for liquid–liquid phase separation
Liquid–liquid phase separation plays an important role in creating cellular compartments and protocells, but designing small-molecule models remains difficult. A peptide-based synthon for liquid–liquid phase separation consisting of two stickers and a flexible, polar spacer has now been presented. Condensates formed by these synthons can concentrate biomolecules and catalyse anabolic reactions.
- Manzar Abbas
- , Wojciech P. Lipiński
- & Evan Spruijt
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News & Views |
Tying peptide ropes
Although the natural lasso peptide microcin J25 remains an elusive target for total chemical synthesis itself, this topologically non-trivial building block has now been used to construct a range of interlocked molecular architectures including rotaxanes, catenanes and daisy chains.
- Jan H. van Maarseveen
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Dynamic covalent self-assembly of mechanically interlocked molecules solely made from peptides
The construction of mechanically interlocked molecules solely made from peptides is a great synthetic challenge because of a lack of effective templating strategies. Now it has been shown that by combining self-assembly and dynamic covalent chemistry, catenanes, daisy chains and other interlocked peptides can be synthesized from genetically engineered building blocks.
- Hendrik V. Schröder
- , Yi Zhang
- & A. James Link
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Article |
Constructing ion channels from water-soluble α-helical barrels
The de novo design of functional membrane proteins is a formidable challenge. Now, water-soluble peptides have been designed that assemble into α-helical barrels with accessible, polar and hydrated central channels. Insights from these structures have been used to produce stable membrane-spanning, cation-selective channels.
- Alistair J. Scott
- , Ai Niitsu
- & Derek N. Woolfson
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Article |
Cellular uptake of large biomolecules enabled by cell-surface-reactive cell-penetrating peptide additives
Robust delivery of proteins into cells is challenging, but it has now been shown that by conjugating arginine-rich cell-penetrating peptides to the surface of cells, proteins containing a cell-penetrating peptide can be delivered efficiently into them. Using a thiol-reactive cell-penetrating peptide enables thiol-containing proteins to be delivered by simple co-incubation.
- Anselm F. L. Schneider
- , Marina Kithil
- & Christian P. R. Hackenberger
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Article |
Illuminating the dark conformational space of macrocycles using dominant rotors
Constrained molecules typically adopt one major conformation and this limitation prevents the study of other energetically less-favourable conformations. Nevertheless, these alternate structures might prove to be useful and it has now been shown that a dominant rotor method can alter the energetic landscape of peptides to create two-well systems with distinct conformational behaviour.
- Diego B. Diaz
- , Solomon D. Appavoo
- & Andrei K. Yudin
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Article |
Predicting the stability of homotrimeric and heterotrimeric collagen helices
Collagen-like peptides can self-assemble into hundreds of closely related triple helices. Now, an algorithm has been developed that predicts the most stable helix and the extent to which it will assemble to the exclusion of the competing helices. This information can help improve the understanding of triple helix design and assembly.
- Douglas R. Walker
- , Sarah A. H. Hulgan
- & Jeffrey D. Hartgerink
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Live cell PNA labelling enables erasable fluorescence imaging of membrane proteins
A method for the covalent labelling of proteins by installing a biostable peptide nucleic acid (PNA) tag has now been developed. The PNA label serves as a generic landing platform that enables the recruitment of fluorescent dyes via nucleic acid hybridization and fluorophore removal by toehold-mediated strand displacement. Imaging of cell surface receptors, including internalized receptors, has been demonstrated using this approach.
- Georgina C. Gavins
- , Katharina Gröger
- & Oliver Seitz
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Ribosomal synthesis and de novo discovery of bioactive foldamer peptides containing cyclic β-amino acids
Cyclic β-amino acids can add useful properties to peptides, such as inducing turn structures or providing resistance to proteases. To harness these properties up to ten consecutive cyclic β-amino acids have now been ribosomally incorporated via genetic code reprogramming into a foldamer peptide library that has been screened for potent binders against a protein target, human factor XIIa.
- Takayuki Katoh
- , Toru Sengoku
- & Hiroaki Suga
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Post-translational formation of strained cyclophanes in bacteria
A series of enzymes that catalyse the formation of strained peptide cyclophanes through a stereospecific C(sp2)–C(sp3) bond have been identified. Crosslinking occurs on three-residue motifs that include tryptophan or phenylalanine to form indole- or phenyl-bridged cyclophanes. These enzymes are widely distributed in nature and represent promising tools for peptide biotechnology.
- Thi Quynh Ngoc Nguyen
- , Yi Wei Tooh
- & Brandon I. Morinaka
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Heteromeric three-stranded coiled coils designed using a Pb(ii)(Cys)3 template mediated strategy
A method to fabricate heterotrimeric three-stranded coiled-coil peptide structures has now been developed using coordination around a Pb(ii) centre. The heterotrimeric structures require only three cysteines that bind to Pb(ii) to form a trigonal pyramidal structure, and the formation of an adjacent cavity in which water can hydrogen bond to the cysteine sulfur atoms.
- Audrey E. Tolbert
- , Catherine S. Ervin
- & Vincent L. Pecoraro
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News & Views |
From soup to peptides
Proteins are biosynthesized from α-amino acids using hefty biological machinery, but the origin of this process on the early Earth is unclear. Now, a bottom-up approach for forming peptides, taking place under mild, prebiotically-plausible conditions, has been developed. This strategy uses α-aminonitrile precursors, bypassing α-amino acids entirely.
- Robert Pascal
- & Irene A. Chen
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Article |
Protein engineering through tandem transamidation
A method for engineering chemically modified proteins has now been developed using a chemoenzymatic cascade of sortase-mediated transpeptidation and protein trans-splicing. Using this one-pot approach enabled the generation of site-specifically modified proteins in vitro and in isolated cell nuclei.
- Robert E. Thompson
- , Adam J. Stevens
- & Tom. W. Muir
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Article |
De novo macrocyclic peptides that specifically modulate Lys48-linked ubiquitin chains
Modulating particular ubiquitin chains using binding molecules is challenging given the diversity of chain lengths and linkages found in vivo. Now, tight binding modulators that are specific to K48-linked ubiquitin chains have been found by combining protein synthesis and screening of macrocyclic peptide ligands.
- Mickal Nawatha
- , Joseph M. Rogers
- & Ashraf Brik
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Article |
Modification and de novo design of non-ribosomal peptide synthetases using specific assembly points within condensation domains
Non-ribosomal peptide synthetases have now been modified and de novo non-ribosomal peptide synthetases constructed using new assembly points within condensation domains. This approach enabled the production of new-to-nature peptides, including some carrying synthetic amino acids, as well as the generation of peptide libraries.
- Kenan A. J. Bozhüyük
- , Annabell Linck
- & Helge B. Bode
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News & Views |
Deciphering bacterial signalling
Bacterial communication is a potential strategy to control bacterial behaviours and thus, attenuate pathogen infectivity; however, identifying the signalling molecules that regulate communication pathways is challenging. Now, a robust strategy to rapidly identify previously unknown signalling peptides has been developed. This approach provides a means to map out and decipher bacterial signalling mechanisms.
- Dominic N. McBrayer
- & Yftah Tal-Gan
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Identification of autoinducing thiodepsipeptides from staphylococci enabled by native chemical ligation
Bacteria communicate through excretion of minute amounts of chemical signalling molecules that affect virulence, biofilm formation and colonization. In staphylococci, these molecules, called autoinducing peptides, are macrocyclic thiolactone-containing peptides. Now, a simple enrichment method, based on chemoselective capture on polymer beads, has been developed that enables the identification of previously unknown autoinducing peptides.
- Bengt H. Gless
- , Martin S. Bojer
- & Christian A. Olsen
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Fluorogenic d-amino acids enable real-time monitoring of peptidoglycan biosynthesis and high-throughput transpeptidation assays
Biosynthesis of peptidoglycan requires carefully orchestrated transpeptidation reactions to maintain the structural integrity of this essential component of the bacterial cell wall. Now, rotor-fluorescent d-amino acids have been shown to enable real-time tracking of these transpeptidation reactions in live bacterial cells. These powerful tools allow visualization of peptidoglycan biosynthesis with high spatiotemporal resolution.
- Yen-Pang Hsu
- , Edward Hall
- & Michael S. VanNieuwenhze
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Article |
Rapamycin-inspired macrocycles with new target specificity
Rapamycin and FK506 are macrocycles that contain an FKBP-binding domain and an effector domain responsible for interacting with their respective targets, mTOR and calcineurin. Now, a 45,000-compound macrocycle library has been synthesized by fusing oligopeptides with synthetic FKBP-binding domains. Screening and subsequent optimization yielded a highly potent FKBP-dependent inhibitor of hENT1.
- Zufeng Guo
- , Sam Y. Hong
- & Jun O. Liu
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Editorial |
Ring binders
Encoded chemical libraries can be used to screen a vast array of compounds against a protein target to identify potent binders. A collection of articles in this issue discuss different methods to increase the chemical space sampled by encoded macrocycle libraries and the advantages that such libraries offer for discovering new drug leads.
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Q&A |
Looking in the library
Ghotas Evindar, Chemistry Group Leader at GlaxoSmithKline, talks with Nature Chemistry about the advantages of using encoded libraries in drug discovery and the challenges these technologies present.
- Russell Johnson
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News & Views |
Shaping molecular diversity
Certain drug targets have been deemed undruggable because of the difficulty in finding pharmacologically useful inhibitors. Now, two teams have developed exciting technologies for the creation of diverse collections of macrocyclic molecules and have demonstrated their usefulness for discovering macrocyclic inhibitors.
- Emil S. Iqbal
- & Matthew C. T. Hartman
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Cyclization of peptides with two chemical bridges affords large scaffold diversities
Crosslinking within peptides containing two pairs of cysteines to form chemical bridges has now been shown to provide rapid access to thousands of different macrocyclic scaffolds in libraries that are easy to synthesize, screen and decode. Applying this strategy to phage-encoded libraries yielded binders with remarkable affinities despite the small molecular mass.
- Sangram S. Kale
- , Camille Villequey
- & Christian Heinis
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A general strategy for synthesis of cyclophane-braced peptide macrocycles via palladium-catalysed intramolecular sp3 C−H arylation
Peptide macrocycles are uniquely suited to engage some challenging biological targets, such as protein–protein interactions. Inspired by the ‘C–H’ cross-linked peptide natural products, a highly efficient and generally applicable strategy for constructing cyclophane-braced peptide macrocycles has been developed. The strategy is based on palladium-catalysed intramolecular C(sp3)–H arylation reactions.
- Xuekai Zhang
- , Gang Lu
- & Gong Chen
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Article |
Ribosomal synthesis and folding of peptide-helical aromatic foldamer hybrids
The extent to which peptide synthesis by the ribosome can tolerate the inclusion of non-peptidic components is not clear. Yet such hybrids would expand the range of ribosomally synthesized structures. Now it has been shown that tRNAs acylated by aromatic foldamers can initiate the ribosomal synthesis of non-cyclic and cyclic foldamer–peptide hybrid molecules. The oligo-aryl segments contain folding information that can control peptide conformation in the hybrids.
- Joseph M. Rogers
- , Sunbum Kwon
- & Ivan Huc
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Article |
Dynamic covalent chemistry enables formation of antimicrobial peptide quaternary assemblies in a completely abiotic manner
Despite advances in peptide synthesis techniques, explicit control over the quaternary structure of synthetic peptides has remained elusive. Now, the dynamic covalent chemistry of hydrazide- and aldehyde-containing peptides has now been shown to enable the formation of unique quaternary structures with topological diversity. Using this method, oligomers were assembled into complex structures showing dramatic enhancements of antimicrobial effectiveness versus Staphylococcus Aureus.
- James F. Reuther
- , Justine L. Dees
- & Eric V. Anslyn
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Article |
Cytosolic antibody delivery by lipid-sensitive endosomolytic peptide
The trapping of antibodies in endosomes often limits their use for intracellular targeting. Now, a single amino acid substitution on a spider-venom peptide has been shown to attenuate the cell membrane lytic activity and enables the selective rupturing of endosomal membranes. The peptide can be used to facilitate the escape of antibodies from endosomes into the cytosol.
- Misao Akishiba
- , Toshihide Takeuchi
- & Shiroh Futaki
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Article |
Entomopathogenic bacteria use multiple mechanisms for bioactive peptide library design
Nature has evolved a variety of different mechanisms to generate chemical diversity; however, the reactions responsible for generating such diverse chemical libraries are often not clear. Now, the mechanisms employed by entomopathogenic bacteria for the biosynthesis of a large family of bioactive peptides have been identified. These include substrate promiscuity, enzyme cross-talk and enzyme stoichiometry.
- Xiaofeng Cai
- , Sarah Nowak
- & Helge. B. Bode
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Article |
Seven enzymes create extraordinary molecular complexity in an uncultivated bacterium
Polytheonamides are giant peptide toxins produced by the uncultivated sponge bacterium Entotheonella factor. The biosynthesis of polytheonamides involves up to 50 post-translational modifications. Now, heterologous expression in Escherichia coli and Rhizobium hosts have shown that a minimalistic, iterative enzyme set introduces this exceptional molecular complexity via epimerizations, C-/N-methylations, hydroxylations, dehydration and proteolytic maturation.
- Michael F. Freeman
- , Maximilian J. Helf
- & Jörn Piel
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News & Views |
Tying up loose ends
Despite their potential as drugs, peptides are generally not cell permeable, which limits their practical applications in medicine. Now, linear peptides have been cyclized by using a heteroaromatic linker. This cyclization both improves passive membrane permeability and stabilizes a biologically relevant secondary structure.
- Fumito Saito
- & Jeffrey W. Bode
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Article |
Oxadiazole grafts in peptide macrocycles
Controlling macrocycle conformation represents a powerful tool for the construction of new bioactive molecules. Now, peptide-based macrocycles bearing a 1,3,4-oxadiazole moiety grafted into their backbone have been synthesized via a new cyclization approach. The resulting cyclic products exhibit conformationally rigid turn structures (stabilized through intramolecular hydrogen bonding) that can display passive membrane permeability.
- John R. Frost
- , Conor C. G. Scully
- & Andrei K. Yudin
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News & Views |
Functional Frankensteins
An artificial esterase with no known natural structural analogues has been formed via the homo-heptameric self-assembly of a designed peptide. This esterase represents the first report of a functional catalytic triad rationally engineered into a de novo protein framework.
- Olga V. Makhlynets
- & Ivan V. Korendovych
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Article |
Total synthesis and structure–activity relationship studies of a series of selective G protein inhibitors
G proteins are the key mediators of G protein-coupled receptor signalling, facilitating a number of important physiological processes. Now, the total synthesis and structure–activity relationship studies have been reported for the only known selective Gq protein inhibitors, the natural cyclic depsipeptides YM-254890 and FR900359.
- Xiao-Feng Xiong
- , Hang Zhang
- & Kristian Strømgaard
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Article |
Peptide tessellation yields micrometre-scale collagen triple helices
Natural collagen contains triple helices that are approximately 1,000 residues in length and cannot be formed by chemical synthesis. Now, short collagen-mimetic peptides that self-assemble into three-stranded helices have been designed. These peptides are inspired by the mathematics of tessellations, and the triple helices formed via this approach match or exceed the length of those found in natural collagen.
- I. Caglar Tanrikulu
- , Audrey Forticaux
- & Ronald T. Raines
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Article |
Oligoarginine peptides slow strand annealing and assist non-enzymatic RNA replication
Identifying a non-enzymatic method of replicating RNA for multiple cycles has been problematic because rapid strand reannealing outcompetes slow non-enzymatic template copying. Now, oligoarginine peptides have been shown to inhibit reannealing while still allowing short primers and activated monomers to bind to the template strand, facilitating the next round of template copying.
- Tony Z. Jia
- , Albert C. Fahrenbach
- & Jack W. Szostak
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Article |
Switchable photooxygenation catalysts that sense higher-order amyloid structures
Selectively degrading the pathogenic, aggregated amyloid state of proteins, without affecting the functional state, is a potential therapeutic strategy for treating amyloid diseases. Now, photooxygenation catalysts that are active only when bound to the cross-β-sheet structure of the amyloid form have been developed.
- Atsuhiko Taniguchi
- , Yusuke Shimizu
- & Motomu Kanai
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Article |
Sequence-defined bioactive macrocycles via an acid-catalysed cascade reaction
Macrocyclic oligomers are a unique structural class of compounds in which the ring size and structure can be tuned through the precise control of the primary sequence. Now, it has been shown that oligothioetheramide (oligoTEA) macrocycles can be synthesized using a one-pot acid-catalysed cascade reaction. Preliminary results indicate that cationic oligoTEAs are promising bactericidal agents.
- Mintu Porel
- , Dana N. Thornlow
- & Christopher A. Alabi
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Review Article |
Expanding the chemical toolbox for the synthesis of large and uniquely modified proteins
Chemical protein synthesis can enable the preparation of proteins containing post-translational modifications or unnatural variations such as D-amino acids. Such modified proteins are not easily fabricated by other methods. This Review provides an overview of the current approaches for the chemical synthesis of proteins.
- Somasekhar Bondalapati
- , Muhammad Jbara
- & Ashraf Brik