Chemical biology articles within Nature Chemistry

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  • Research Briefing |

    A non-radical proximity labelling platform — BAP-seq — is presented that uses subcellular-localized BS2 esterase to convert unreactive enol-based probes into highly reactive acid chlorides in situ to label nearby RNAs. When paired with click-handle-mediated enrichment and sequencing, this chemistry enables high-resolution spatial mapping of RNAs across subcellular compartments.

  • Article |

    RNA localization is key to regulating cellular function but is challenging to measure in an unbiased manner. Now a combination of enol-masked acylating probes with a bioorthogonal esterase to locally unmask them provides a non-radical RNA proximity labelling platform—termed BAP-seq—that enables the generation of high-resolution spatial maps of RNA.

    • Shubhashree Pani
    • , Tian Qiu
    •  & Bryan C. Dickinson

  • Article
    | Open Access

    Negatively charged lysine acylations—malonylation, succinylation and glutarylation—impact protein structure and function, which can affect cellular processes. Now temporarily masked thioester derivatives of succinylation and glutarylation can be used for site-specific modification of diverse bacterial and mammalian proteins, which can facilitate the study of how these lysine modifications impact enzymatic activity and control protein–protein and protein–DNA interactions.

    • Maria Weyh
    • , Marie-Lena Jokisch
    •  & Kathrin Lang

  • News & Views |

    Expansion of the genetic code can enable precise manipulation of proteins through selective functionalization of specific residues. Now, control of tryptophan interactions in proteins can be established by encoding of a vinyl-caged tryptophan analogue that can be selectively decaged to rescue protein activity.

    • Aidan K. Haney
    •  & T. Ashton Cropp

  • Article |

    Ribosomally synthesized and post-translationally modified peptides (RiPPs) can have vast structural diversity and biological functions enabled by disparate post-translational modifications (PTMs). However, unconventional PTMs derived from non-RiPP biosynthesis are rarely reported. Now a class of lipopeptides featuring a distinct fatty-acyl-modified N terminus and the responsible RiPP/fatty-acid hybrid biosynthetic machinery have been characterized.

    • Hengqian Ren
    • , Chunshuai Huang
    •  & Huimin Zhao

  • Article |

    Developing a generalizable method for blocking and rescuing tryptophan (Trp) interactions would enable the gain-of-function manipulation of various Trp-containing proteins but has so far been challenging. Now a genetically encoded N1-vinyl-caged Trp capable of rapid and bioorthogonal decaging enables site-specific activation of Trp on a protein of interest within living cells.

    • Yuchao Zhu
    • , Wenlong Ding
    •  & Peng R. Chen

  • Article
    | Open Access

    Design strategies that possess both biological relevance and structural diversity may lead to compound collections that are enriched in diverse bioactivities. Now a diverse pseudo-natural product design principle has been established to efficiently explore biologically relevant chemical space. Through dearomatization reactions, a compound collection enriched in both structural and biological diversity was rapidly generated.

    • Sukdev Bag
    • , Jie Liu
    •  & Herbert Waldmann

  • Article |

    Lipidomics aims to uncover lipid functions in biological systems and disease. Quantifying lipids is challenging due to highly diverse chemical structures. Here a diazobutanone-assisted isobaric labelling method is developed that relies on diazobutanone and isobaric mass tags to target phosphate- and sulfate-containing lipids, enabling multiplexed lipidomic quantification in complex mixtures.

    • Ting-Jia Gu
    • , Peng-Kai Liu
    •  & Lingjun Li

  • Research Briefing |

    Covalent protein conjugation facilitates the study of biological processes and the synthesis of therapeutic biomacromolecules. A method that uses vinyl thianthrenium reagents for the site-selective formation of highly reactive episulfonium species on proteins is demonstrated. These in situ-formed intermediates react with diverse nucleophiles, providing access to protein conjugates in one step without purification.

  • Research Briefing |

    A protein-templated selection approach has been developed for the discovery of full ligands from dual-pharmacophore DNA-encoded libraries by incorporating fragment linking into the selection process. The performance of this method was demonstrated with selections against protein–protein interaction and protein–DNA interaction targets, through which potent and selective inhibitors were identified.

  • Article |

    Dual-pharmacophore DNA-encoded chemical libraries enable the identification of two synergistic binders for a biological target, but subsequent linking of this pair is required to obtain a full ligand, which can be challenging. Here we report a protein-templated selection of DNA-encoded dynamic library that can identify full ligands from fragment libraries without the need for subsequent fragment linking.

    • Yu Zhou
    • , Wenyin Shen
    •  & Xiaoyu Li

  • In Your Element |

    Thomas Kruse and Søren Østergaard reflect on the development of the GLP-1 analogue, semaglutide, which is reshaping peptide therapeutics in type 2 diabetes, weight management, and beyond.

    • Thomas Kruse
    •  & Søren Østergaard

  • Article |

    Cells spatially organize biochemical reactions within membrane-bound and membraneless compartments. The extent to which intrinsically disordered proteins themselves can form discrete compartments or condensed phases is poorly understood. Now a pair of model IDRs that display orthogonality in condensation and the chain features governing selective assembly have been identified.

    • Rachel M. Welles
    • , Kandarp A. Sojitra
    •  & Matthew C. Good

  • Article |

    The lack of effective methods for mirror-image (d-) protein sequencing hampers the development of mirror-image biology systems and related applications. Now, total chemical synthesis of mirror-image trypsin enables the sequencing of long d-peptides and d-proteins, which may facilitate applications of d-peptides and d-proteins as potential therapeutic and informational tools.

    • Guanwei Zhang
    •  & Ting F. Zhu

  • Article
    | Open Access

    Natural products discovery remains an ongoing challenge. Now, halide depletion offers a complementary approach to discover natural products whose biosynthesis requires halides, including products of cryptic halogenation. Halide depletion reveals that nostochlorosides, the products of an orphan biosynthetic gene cluster in Nostoc punctiforme, are polymerized by a halide-displacing etherifying enzyme.

    • Nathaniel R. Glasser
    • , Dongtao Cui
    •  & Emily P. Balskus

  • Thesis |

    Given the fraught history of fluorine, Michelle Francl wonders what made medicinal chemists consider fluorine derivatives?

    • Michelle Francl

  • News & Views |

    As the need for specific fluorescent probes that enable high sensitivity and super-resolution imaging experiments continues to grow, it is imperative to develop new, well-characterized methods to modulate the emission of fluorophores. Now, a general platform affords visible-to-NIR fluorogenic fluorophores by engineering a simple cyclization event into cyanine dyes.

    • Quintashia D. Wilson
    •  & Ellen M. Sletten

  • Article |

    Current proteolysis-targeting chimeras can promote the ubiquitination and subsequent degradation of both target and off-target proteins by inducing their respective proximity with the cereblon ubiquitin ligase. Now, by developing and deploying an off-target profiling platform, ‘bumped proteolysis-targeting chimeras’ can maintain on-target degradation efficacy with reduced off-targets.

    • Tuan M. Nguyen
    • , Vedagopuram Sreekanth
    •  & Amit Choudhary

  • Article |

    Current electrochemical-based protein labelling methods suffer from limited site-selectivity and off-target reactivity owing to required radical/electrophilic reagents. Now an electrochemical strategy enables chemoselective labelling of proteins at a site-specifically incorporated 5-hydroxytryptophan residue using aromatic amines as coupling partners. This approach works on various proteins, including a full-length antibody, and is compatible with established click reactions.

    • Conor Loynd
    • , Soumya Jyoti Singha Roy
    •  & Abhishek Chatterjee

  • Article
    | Open Access

    Enzyme-initiated polymerization-induced self-assembly has been used to generate various biomimetic structures. Now, myoglobin’s activity is used for biocatalytic polymerization-induced self-assembly to generate vesicular artificial cells. As various cargoes can be encapsulated during polymerization, these artificial cells are capable of protein expression and can act as microreactors for distinct enzymatic reactions.

    • Andrea Belluati
    • , Sètuhn Jimaja
    •  & Nico Bruns

  • Article
    | Open Access

    Polymethine dyes are bright and red-shifted fluorophores that lack an intrinsic turn-on mechanism, which leads to non-specific staining when applied to biological samples. Now the fluorescence of polymethine dyes was masked through an intracellular cyclization strategy that gets reversed upon binding an intended macromolecular target, providing specificity for live-cell imaging.

    • Annabell Martin
    •  & Pablo Rivera-Fuentes

  • Research Briefing |

    To develop covalent inhibitors with high potency and low off-target effects, combinatorial approaches that search for candidates from large libraries are desired. Here, sulfur(VI) fluoride exchange (SuFEx) in vitro selection is established for the evolution of covalent aptamers from trillions of SuFEx-modified oligonucleotides. Through this technique, covalent aptamers with optimally balanced selectivity and reactivity are identified.

  • News & Views |

    Site-specific modification of RNA in cells is crucial for analysis and functional investigations. Natural enzymes that promote RNA methylation using S-adenosyl-l-methionine (SAM) exist, but leveraging these proteins for RNA modification is limited by cell permeability, stability and specificity of their substrates. Now, a de novo ribozyme that acts on a stabilized and cell-permeable SAM analogue enables site-specific RNA modification with a click handle in living cells.

    • Nicolas V. Cornelissen
    •  & Andrea Rentmeister

  • Article |

    Nucleoside diphosphates and triphosphates impact nearly every aspect of biochemistry. Now, a modular, reagent-based platform has been developed to enable the stereocontrolled and scalable synthesis of a library of such molecules. This operationally simple approach provides access to pure stereoisomers of nucleoside α-thiodiphosphates and α-thiotriphosphates.

    • Hai-Jun Zhang
    • , Michał Ociepa
    •  & Phil S. Baran

  • Article
    | Open Access

    Phase separation is being revealed as important in many biological processes. Most attempts to mimic and deconstruct this use engineered natural proteins. Now it is shown that de novo proteins can be designed from first principles to undergo liquid–liquid phase separation in cells, with the potential to organize multi-enzyme pathways.

    • Alexander T. Hilditch
    • , Andrey Romanyuk
    •  & Derek N. Woolfson

  • News & Views |

    Medicinal chemistry efforts typically focus on drug–protein interactions and overlook RNA binding as a source of off-target pharmacology. Now, a new method has been developed to map the interactions of small-molecule drugs with RNA in cells and characterize how these interactions can exert functional effects.

    • Christopher R. Fullenkamp
    •  & John S. Schneekloth Jr

  • Article
    | Open Access

    Ribozyme-mediated post-transcriptional RNA modification is a powerful method for site-specific RNA labelling and analysis of RNA functions. Now, an alkyltransferase ribozyme—termed SAMURI—has been shown to catalyse the transfer of a propargyl group from a stabilized synthetic S-adenosylmethionine analogue to a specific adenosine on the target RNA within cells.

    • Takumi Okuda
    • , Ann-Kathrin Lenz
    •  & Claudia Höbartner

  • Article
    | Open Access

    Molecular systems with coincident cyclic and superhelical symmetry axes have considerable advantages for materials design as they can be lengthened or shortened by changing the length of the monomers. Now a systematic approach to generate modular repeat protein oligomers with combined symmetry that can be extended by repeat propagation has been developed.

    • Neville P. Bethel
    • , Andrew J. Borst
    •  & David Baker

  • Article |

    Now a reactivity-based RNA profiling strategy can measure the global off-target transcriptome interactions of small-molecule drugs at single-nucleotide resolution. Using this approach, three FDA-approved drugs were evaluated, uncovering pervasive drug–RNA interactions and interactions that perturb RNA functions in cells.

    • Linglan Fang
    • , Willem A. Velema
    •  & Eric T. Kool

  • Article
    | Open Access

    Three-protein conjugates, which have so far been produced using protein-engineering strategies, can now be generated using a chemical approach that enables the addition of small-molecule functionality. Checkpoint inhibitory T cell engagers (CiTEs) were assembled and shown to have enhanced in vitro potency compared to a traditional T cell engager.

    • Peter A. Szijj
    • , Melissa A. Gray
    •  & Vijay Chudasama

  • Article |

    Most chemoproteomic screening approaches are indirect. Now, a chemoproteomic platform based on chiral sulfonyl fluoride probes has been developed for the direct identification of probe-modified tyrosines and lysines in live cells. Stereoselective modification by structurally diverse probes was observed for 634 tyrosines and lysines across functionally diverse protein sites.

    • Ying Chen
    • , Gregory B. Craven
    •  & Jack Taunton

  • Article |

    The kinetics of liquid–liquid phase separation (LLPS) in cell-like confinements remains poorly understood. Now it has been shown that it involves complex interplay between the incipient phases and the membrane boundary, which arrests phase coarsening, deforms the membrane and couples LLPS with lipid phase separation.

    • Wan-Chih Su
    • , James C. S. Ho
    •  & Atul N. Parikh

  • Article
    | Open Access

    An enzymatic reaction installs endogenous β-amino acids in proteins with unique reactivity. Now it has been shows that this reaction can be used for site-specific modification with tetrazine dienophiles to introduce labels onto target proteins. Applications include generation of a radiolabel chelator-modified Her2-binding Affibody and intracellular, fluorescently labelled cell division protein FtsZ.

    • Daniel Richter
    • , Edgars Lakis
    •  & Jörn Piel

  • Article |

    Microtubules carry patterns of post-translational modifications that are important for the regulation of key cellular processes. Now a semi-synthetic method facilitates the production of tubulins with defined post-translational modifications. Using these designer tubulins, polyglutamylation of α-tubulin is found to promote its detyrosination by enhancing the activity of the carboxypeptidase vasohibin/small vasohibin-binding protein.

    • Eduard Ebberink
    • , Simon Fernandes
    •  & Charlotte Aumeier

  • Article |

    Stabilization of RNAs for storage, transport and biological application remains a profound challenge. Now, it has been shown that reversible 2′-OH acylation with easily accessible acylimidazoles unlocks efficient protection of RNA. RNA can be deprotected by non-basic nucleophiles or spontaneously in cells to restore RNA functions.

    • Linglan Fang
    • , Lu Xiao
    •  & Eric T. Kool

  • Article |

    Two glycosylated enzymes, EupfF and PycR1, have now been characterized and shown to independently catalyse the tandem intermolecular [4 + 2] cycloaddition in the biosynthesis of bistropolone-sesquiterpenes. Through analysis of enzyme–substrate co-crystal structures, together with computational and mutational studies, the origins of their catalytic activity and stereoselectivity were elucidated.

    • Jiawang Liu
    • , Jiayan Lu
    •  & Youcai Hu

  • Article |

    Celastrol is a potent anti-obesity agent found in the root of Tripterygium wilfordii, but its medicinal application is compromised by limited availability. Now, by combining plant biochemistry with metabolic engineering and chemistry, the biosynthetic pathway of celastrol has been elucidated and has afforded its scalable production in yeast.

    • Yong Zhao
    • , Nikolaj L. Hansen
    •  & Sotirios C. Kampranis

  • Research Briefing |

    Challenges in the synthesis of heparan sulfate (HS) glycosaminoglycans have limited access to defined HS oligosaccharides bearing a diverse array of sulfation sequences. A concise, divergent synthetic approach now provides a library of 64 HS tetrasaccharides displaying a comprehensive set of sulfation sequences, offering insight into the elusive sulfation code of glycosaminoglycans.

  • Article |

    Contrary to agonist binding being the sole driver for β2-adrenergic receptor (β2AR) activation, molecular metadynamics simulations now reveal a distinct activation mechanism. Coupling β2AR with its cognate Gs protein induces considerable structural changes, activating both proteins. Gs opens its GDP binding pocket while β2AR undergoes expansion.

    • Amirhossein Mafi
    • , Soo-Kyung Kim
    •  & William A. Goddard III

  • Article |

    Large collections of defined glycosaminoglycan (GAG) structures have been synthetically challenging to obtain but are required to understand this important class of biomolecules. Now, an efficient platform for synthesizing large libraries of heparan sulfate oligosaccharides has been developed, providing a detailed view into the sulfation code of GAGs.

    • Lei Wang
    • , Alexander W. Sorum
    •  & Linda C. Hsieh-Wilson

  • Research Briefing |

    Protein translation is the ultimate paradigm for sequence-defined polymer synthesis. To introduce non-canonical monomers into the genetic code of living organisms, pairs of biomolecules known as aminoacyl-tRNA synthetases (aaRSs) and transfer RNAs (tRNAs) are required. The discovery and engineering of five such pairs, that do not interfere with each other or the aaRS–tRNA pairs of a bacterial host, sets the stage for highly modified genetically encoded biopolymers.

  • Article |

    The covalent capture of a ligand by its target protein(s) is important for drug-target identification. Now an electrochemically active warhead—diazetidinone—can be leveraged in a chemoproteomics platform for electroaffinity labelling of a ligand’s target protein to afford target-ligand identification in live cells.

    • Yu Kawamata
    • , Keun Ah Ryu
    •  & Phil S. Baran

  • Article
    | Open Access

    Fluorescent sensors that are responsive only in a specific subcellular location have remained elusive. Now, a chemogenetic sensing platform has been developed to sense glutathione in a user-defined organelle of interest. These tools enable quantitative studies of subcellular glutathione homeostasis using visible or near-infrared wavelengths.

    • Sarah Emmert
    • , Gianluca Quargnali
    •  & Pablo Rivera-Fuentes

  • Article |

    Mutually orthogonal aminoacyl transfer RNA synthetase/transfer RNA pairs are required for genetically encoding non-canonical amino acids into proteins, as well as for the encoded cellular synthesis of polymers and macrocycles; however, the scalable discovery of such pairs is challenging. A quintuply orthogonal set of pyrrolysyl-tRNA synthetase/pyrrolysyl-tRNA pairs has now been generated through tRNA screening, engineering and directed evolution.

    • Adam T. Beattie
    • , Daniel L. Dunkelmann
    •  & Jason W. Chin

  • Article |

    Acylhydrazones are often found in compounds across screening databases, and numerous bioactive acylhydrazones exist. This functional group can isomerize between E and Z in response to light or upon exposure to thiols. Now, E/Z isomerization is found to impact activities of bioactive acylhydrazones and should be routinely analysed.

    • Zhiwei Zhang
    • , Giang N. T. Le
    •  & G. Andrew Woolley

  • Article
    | Open Access

    Genetic code expansion to incorporate non-α-amino acid monomers is limited by predictability of monomer reactivities in the context of the ribosome. Now the use of metadynamics simulations of pre-attack monomers in the ribosomal peptidyl transferase centre provides insight on whether an A-site monomer is likely to be reactive.

    • Zoe L. Watson
    • , Isaac J. Knudson
    •  & Ara M. Abramyan

  • Article |

    Incorporating polar residues into hydrophobic protein channel pores facilitates selective proton transport. Now, classical and multiscale reactive molecular dynamics simulations of designed channels reveal dynamic water wires within the channel lumen that are proton conductive according to structural and functional validation. These results provide some guiding principles for biological and engineered proton conduction.

    • Huong T. Kratochvil
    • , Laura C. Watkins
    •  & William F. DeGrado

  • Article
    | Open Access

    Ribosomal incorporation of non-α-amino acid monomers into proteins is largely restricted to in vitro translation. Now, pyrrolysyl-transfer RNA synthetase variants have been shown to acylate tRNAs with α-thio acids, malonic acids, and N-formyl amino acids. This work represents a key step towards the programmed ribosomal synthesis of sequence-defined non-protein polymers in cellulo.

    • Riley Fricke
    • , Cameron V. Swenson
    •  & Alanna Schepartz

  • News & Views |

    Constructing aptamers with desired target-binding affinities may lead to new applications but is challenging. Now, a new method using a high-dimensional microfluidic approach enables quantitative isolation of aptamers with programable binding affinities.

    • Ping Song
    •  & Chunhai Fan

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