Chemical biology articles within Nature Chemistry

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  • Article
    | Open Access

    Entomopathogenic nematodes carrying Xenorhabdus and Photorhabdus bacteria prey on insect larvae in the soil. Now, a comprehensive analysis of the bacterial genome has revealed ubiquitous and unique families of biosynthetic gene clusters. Evaluation of the bioactivity of the natural products expressed by the most prevalent cluster families explains the functional basis of bacterial natural products involved in bacteria–nematode–insect interactions.

    • Yi-Ming Shi
    • , Merle Hirschmann
    •  & Helge B. Bode

  • Article |

    Soft bioelectronic devices have exciting potential applications in robotics, computing and medicine, but they are typically restricted by the requirement for tethers or stiff electrodes. Now, a synthetic nerve has been developed that is bioinspired, wireless and powered by light. By patterning functionalized lipid membrane compartments, information was directionally conveyed using electrochemical signals.

    • Charlotte E. G. Hoskin
    • , Vanessa Restrepo Schild
    •  & Hagan Bayley

  • In Your Element |

    Christine M. Le takes a look at 2-[18F]fluoro-2-deoxyglucose and explains how this radioactive sugar could help to save your life.

    • Christine M. Le

  • Article |

    Combinatorial high-throughput methodologies can accelerate screening and discovery in biochemistry and biomedical sciences, but they often rely on large-scale analyses, making them time-consuming and expensive. Now, DNA-mediated fusion of single liposomes has been shown to enable the spatially resolved and parallel cargo delivery of subattolitre volumes in a stochastic order of succession.

    • Mette Galsgaard Malle
    • , Philipp M. G. Löffler
    •  & Nikos S. Hatzakis

  • Review Article |

    Viruses use the cellular machinery of their host organism to reproduce. This Review discusses how [FeS] cluster-containing proteins activate, support and modulate the innate immune response to restrict viral infections as well as highlighting how some of these proteins simultaneously support the replication of viruses.

    • Kourosh Honarmand Ebrahimi
    • , Simone Ciofi-Baffoni
    •  & Fraser A. Armstrong

  • Article
    | Open Access

    Phase-separated compartments have long been proposed as precursors to cellular life. Now, it has been shown that RNA–peptide protocells are more robust when formed using shorter (rather than longer) peptides, and that peptide sequence determines the functional materials properties of these compartments.

    • Juan M. Iglesias-Artola
    • , Björn Drobot
    •  & Moritz Kreysing

  • Article |

    Reliable intracellular delivery of antibodies is one of the grand challenges in biomedical research, with the potential to address unmet clinical needs or to enable basic research. Now, it has been shown that tricyclic peptide complexes can transport functional antibodies into the cytoplasm and nucleus of cells to specifically target intracellular proteins.

    • Ole Tietz
    • , Fernando Cortezon-Tamarit
    •  & Katherine A. Vallis

  • Perspective |

    DNA-encoded libraries can be applied in a diverse range of applications beyond simple binding assays. This Perspective covers the recent progress in using DNA-encoded chemical libraries to investigate complex biological targets and discusses their potential to identify structures that elicit function or possess other useful properties.

    • Yiran Huang
    • , Yizhou Li
    •  & Xiaoyu Li

  • Article |

    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

  • Article |

    Threose nucleic acid (TNA) is a potential RNA evolutionary progenitor and a nuclease-resistant synthetic genetic polymer. Now, a TNA catalyst that cleaves RNA has been identified in vitro. The TNA catalyst shows strong sequence selectivity towards a mutant RNA substrate involved in drug resistance, resulting in selective gene silencing in eukaryotic cells.

    • Yueyao Wang
    • , Yao Wang
    •  & Hanyang Yu

  • Article |

    A dual cellular-then-heterogeneous catalysis strategy has been used to produce olefins from glucose. 3-Hydroxy acids are made using an engineered microbial host. A hydrolytic step then provides the driving force for fatty acid deoxygenation by simple heterogeneous Lewis acid catalysis. This decarboxylation–dehydration route to olefinic products avoids the need for an additional redox input typically required for deoxygenation of unmodified fatty acids.

    • Zhen Q. Wang
    • , Heng Song
    •  & Michelle C. Y. Chang

  • Article |

    The systemic discovery of metal–small-molecule complexes from biological samples is a difficult challenge. Now, a method based on liquid chromatography and native electrospray ionization mass spectrometry has been developed. The approach uses post-column pH adjustment and metal infusion combined with ion identity molecular networking, and a rule-based informatics workflow, to interrogate small-molecule–metal binding.

    • Allegra T. Aron
    • , Daniel Petras
    •  & Pieter C. Dorrestein

  • Article |

    Biosynthesis of aromatic amines typically uses glutamic acid or glutamine as the nitrogen donor. Now, a biosynthetic pathway to aromatic amines has been reported that uses glycyl-tRNA as the nitrogen donor. The myosin-targeting ammosamide is made via a pathway that involves the post-translational modification of a tryptophan, which is added to the end of a peptide in a tryptophanyl-tRNA-dependent step.

    • Page N. Daniels
    • , Hyunji Lee
    •  & Wilfred A. van der Donk

  • News & Views |

    Phase separation offers a fundamental mechanism for organization and compartmentalization. Now, peptide-based synthons have been shown to form catalytically active coacervates providing a stepping stone for creating synthetic primitive cells.

    • Samrat Mukhopadhyay

  • Article |

    Imaging-based companion diagnostics can provide real-time information to match therapies to patients; however, glutathione is abundant in most cells, making it an unlikely candidate for companion diagnosis. Now, a chemical probe has been developed that can detect elevated glutathione concentrations via photoacoustic imaging. Using this probe enables normal and pathological states in a lung cancer model to be distinguished.

    • Melissa Y. Lucero
    •  & Jefferson Chan

  • Article |

    Natural products are produced by living organisms practising nature’s chemical transformations. Now, an unnatural product has been generated by creating hybrid biosynthetic microorganisms. These microorganisms combine an unnatural chemical transformation—catalysis by an artificial metalloenzyme containing an iridium-based, unnatural cofactor—with a natural biosynthetic pathway within the same cell.

    • Jing Huang
    • , Zhennan Liu
    •  & John F. Hartwig

  • Thesis |

    Michelle Francl reminds #ChemistsWhoCook to look at the chemistry behind the cooking.

    • Michelle Francl

  • Article |

    Triphenylphosphonium ylides (Wittig reagents) that selectively react with sulfenic acids—a pivotal post-translational cysteine modification in redox biology—are developed. This bioconjugation method enables a site-specific proteome-wide stoichiometry analysis of S-sulfenylation, and visualization of redox-dependent changes in mitochondrial cysteine oxidation and the redox-triggered generation of triphenylphosphonium for the controlled delivery of small molecules to mitochondria.

    • Yunlong Shi
    • , Ling Fu
    •  & Kate S. Carroll

  • Article |

    A deep chemical proteomic investigation of diverse aminophilic electrophiles has identified ligandable lysines across a wide range of human proteins. The proteins cover different functional and structural classes, and the aminophilic electrophiles include compounds that disrupt protein–protein and protein–RNA interactions. This dataset provides a proteome-wide atlas of lysine-reactive chemistry.

    • Mikail E. Abbasov
    • , Madeline E. Kavanagh
    •  & Benjamin F. Cravatt

  • News & Views |

    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

  • Article |

    Non-canonical amino acids can be incorporated into proteins through translation of orthogonal mRNAs. Now, automating the design of orthogonal mRNAs—which are more selectively and efficiently translated—in combination with compact orthogonal aminoacyl-tRNA synthetase/tRNA expression systems, enables the incorporation of four distinct non-canonical monomers via a 68-codon genetic code.

    • Daniel L. Dunkelmann
    • , Sebastian B. Oehm
    •  & Jason W. Chin

  • Article |

    Computationally designed enzymes can be substantially improved by directed evolution. Now, it has been shown that evolution can introduce a dynamic network that selectively tightens the transition-state ensemble, giving rise to a negative activation heat capacity. Targeting such transition state conformational dynamics may expedite de novo enzyme creation.

    • H. Adrian Bunzel
    • , J. L. Ross Anderson
    •  & Adrian J. Mulholland

  • Article |

    Machine learning has now been shown to enable the de novo design of abiotic nuclear-targeting miniproteins. To achieve this, high-throughput experimentation was combined with a directed evolution-inspired deep-learning approach in which the molecular structures of natural and unnatural residues are represented as topological fingerprints. The designed miniproteins, called Mach proteins, are non-toxic and can efficiently deliver antisense cargo in mice.

    • Carly K. Schissel
    • , Somesh Mohapatra
    •  & Bradley L. Pentelute

  • News & Views |

    The origin and evolution of translational machinery — which produces a specific peptide from an RNA sequence — is a major unsolved puzzle in prebiotic chemistry. Now, the coupling of amino acids directed by RNA templates in the absence of a ribosome provides clues on how this protein synthesis process might have started.

    • Ya Ying Zheng
    •  & Jia Sheng

  • News & Views |

    Nucleic acids can adopt G-quadruplex folds whose cellular roles remain poorly defined. Synthesis of new probes has now enabled the identification of human proteins that interact with G-quadruplexes. This could provide new clues to decipher the function of these curious folds.

    • Aaron M. Fleming
    •  & Cynthia J. Burrows

  • Article
    | Open Access

    DNA–protein interactions are essential to genome function, but they are challenging to map in a cellular environment. Now, a chemical proteomics approach, which uses DNA G-quadruplex-specific ligands containing a photocrosslinking motif, has enabled the systematic identification of DNA G-quadruplex-binding proteins in live cells.

    • Xiaoyun Zhang
    • , Jochen Spiegel
    •  & Shankar Balasubramanian

  • Article |

    The molybdenum cofactor (Moco) is found in the active site of numerous enzymes, but the mechanism of molybdate insertion is not clear. Now, the mechanism of the final maturation step, in which adenylated molybdopterin and molybdate are the substrates, has been revealed. X-ray crystallography of an Mo-insertase identified adenylated Moco as an unexpected intermediate in this reaction sequence.

    • Corinna Probst
    • , Jing Yang
    •  & Tobias Kruse

  • Article |

    Regioselective chemical modification of wild-type proteins remains challenging. Now, by harnessing the varied SOMOphilicity of native tyrosine residues through photoredox catalysis, a site-selective bioconjugation method has been developed. This technology directly incorporates bioorthogonal formyl groups in one step, forming structurally defined fluorescent conjugates that can be rapidly diversified to biorelevant products.

    • Beryl X. Li
    • , Daniel K. Kim
    •  & David W. C. MacMillan

  • Article |

    Methods to detect and identify bacteria typically rely on enrichment steps such as bacterial culture and nucleic acid amplification. Now, an assay for detecting bacteria based on a two-channel electrical chip that combines electroactive DNAzymes with an electrochemical readout, has been developed. This assay enables reagentless and culture-free detection of bacteria in clinical samples.

    • Richa Pandey
    • , Dingran Chang
    •  & Leyla Soleymani

  • Article |

    Droplet interface bilayer measurements have now shown that membranes formed from chiral phospholipid bilayers are enantioselectively permeable to chiral amino acids. The results show that membrane stereochemistry is necessary and sufficient to drive such enantioselective transport, presenting a new potential route to homochirality. These findings could also have implications for pharmacokinetics and drug design.

    • Juan Hu
    • , Wesley G. Cochrane
    •  & Brian M. Paegel

  • Article |

    Prodrugs offer one route to treat cancer, but they require activation once they have been delivered to the tumour. Now, a simultaneous chemo-radiotherapy strategy has been demonstrated in mice that uses gamma or X-ray irradiation to locally activate an anticancer prodrug.

    • Jin Geng
    • , Yichuan Zhang
    •  & Mark Bradley

  • News & Views |

    Phage display enables screening of billions of peptides comprised mainly of natural amino acids. Now, a method to attach and encode a range of structurally diverse compounds has been reported. This method can expand the chemical space covered by phage display peptide libraries.

    • Christian Heinis

  • News & Views |

    The cell membrane acts as a border that restricts uptake of extracellular proteins. Now, peptide chemists have developed two new approaches for transporting functional and biologically relevant proteins across the cellular border by anchoring cyclic polyarginine peptides on the cell membrane.

    • Jan Vincent V. Arafiles
    •  & Shiroh Futaki

  • News & Views |

    DNA-encoded libraries are a powerful tool to identify hit compounds for drug discovery. Now, two papers have reported new advances in this technology. One paper reports a method to screen for binders inside a living cell, and the other investigates the effects of stereo- and regiochemistry on ligand discovery.

    • Minsoo Song
    •  & Gil Tae Hwang

  • Article |

    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

  • News & Views |

    Although critically important for protein function, post-translational modifications are complex and notoriously difficult to study. Now, the effects of O-GlcNAcylation on chaperone activity and the accompanying inhibition of amyloid fibril formation have been revealed, potentially yielding new routes to combat neurodegeneration.

    • Sheena E. Radford
    •  & Theodoros K. Karamanos

  • Article |

    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

  • Article |

    Voltage imaging is a powerful technique for studying electrical signalling in neurons. A palette of bright and sensitive voltage indicators has now been developed via enzyme-mediated ligation and Diels–Alder cycloaddition. Among these, a far-red indicator faithfully reports neuronal action potential dynamics with an excitation spectrum orthogonal to optogenetic actuators and green/red-emitting biosensors.

    • Shuzhang Liu
    • , Chang Lin
    •  & Peng Zou

  • Article |

    DNA G-quadruplexes can adopt a variety of secondary structures, but it is challenging to identify and classify them quickly. Multivariate analysis of different fluorescence enhancements—generated from an arrayed suite of synthetic hosts and cationic dyes—enables discrimination between G-quadruplex structures of identical length and similar topological types.

    • Junyi Chen
    • , Briana L. Hickey
    •  & Wenwan Zhong

  • News & Views |

    The therapeutic applications of DNAzymes are limited because of their low effectiveness in vivo. Now, a promising approach for constructing DNAzymes that show high gene-silencing efficiency in mammalian cells has been developed. This approach incorporates chemical modifications into an existing DNAzyme scaffold.

    • Yifei Zhou
    •  & Chuanzheng Zhou

  • Article |

    O-methyl nitronate is a rare functional group in natural products. Now, the biosynthetic pathway to O-methyl nitronate, which involves O-methylation of a peptidyl carrier protein (PCP)-tethered nitronate, has been revealed. In some bacteria, the same PCP-tethered nitronate is shown to be oxidized by nitronate monooxygenases to provide nitrite and a PCP-tethered glyoxylate.

    • Hai-Yan He
    •  & Katherine S. Ryan

  • Article |

    RNA-cleaving DNA enzymes (DNAzymes) have the potential to function as therapeutic agents by silencing the expression of disease-associated proteins. Xeno-nucleic acids were used to improve the catalytic activity and biological stability of a highly evolved DNAzyme known as 10–23. The enzyme exhibits a robust multiple-turnover activity in cultured mammalian cells.

    • Yajun Wang
    • , Kim Nguyen
    •  & John C. Chaput

  • Article |

    The specificity of human and animal viruses that engage with O-acetylated sialic acids has now been probed using a collection of O-acetylated sialoglycans obtained by diversification of trisaccharide precursors with viral haemagglutinin–esterases. The results revealed host-specific patterns of receptor recognition and showed that human respiratory viruses uniquely employ 9-O-acetylated α2,8-linked disialosides as receptors.

    • Zeshi Li
    • , Yifei Lang
    •  & Geert-Jan Boons

  • Article |

    The post-translational modification O-GlcNAc on amyloid-forming proteins can inhibit their aggregation. Now, it has been shown that O-GlcNAc modification of small heat shock proteins HSP27, αA- and αB-crystallin can increase their anti-amyloid activity and block the amyloid formation of both α-synuclein and Aβ(1–42). A mechanism for this protective effect based on decreased physical interactions is also proposed.

    • Aaron T. Balana
    • , Paul M. Levine
    •  & Matthew R. Pratt

  • Meeting Report |

    The confined geometry of nanopores enables a wealth of chemistry and analysis to be conducted at the single-molecule scale. Yi-Lun Ying, Aleksandar P. Ivanov and Vincent Tabard-Cossa report on recent developments discussed at the 2020 Nanopore Electrochemistry Meeting.

    • Yi-Lun Ying
    • , Aleksandar P. Ivanov
    •  & Vincent Tabard-Cossa

  • Article |

    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

  • Article |

    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

  • Article |

    A de novo designed zinc-binding protein has been converted into a highly active, stereoselective catalyst for a hetero-Diels–Alder reaction. Design and directed evolution were used to effectively harness Lewis acid catalysis and create an enzyme more proficient than other reported Diels–Alderases.

    • Sophie Basler
    • , Sabine Studer
    •  & Donald Hilvert

  • News & Views |

    Sophisticated drug delivery systems are as essential to modern medicine as drugs themselves. Now, polymer mechanochemistry in sonicated solutions has been used to activate drugs in three different systems. These results offer a promising approach that can be tailored to diverse molecular structures of modern pharmaceuticals.

    • Roman Boulatov

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