Chemical tools articles within Nature Communications

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• Article
  02 April 2024 | Open Access

  An all-in-one tetrazine reagent for cysteine-selective labeling and bioorthogonal activable prodrug construction

  Prodrugs have the potential for improving therapeutic index and expanding drug targets, but current prodrug activation strategies that are responsive to endogenous stimuli can result in unintended drug release and systemic toxicity. Here, the authors report 3-vinyl−6-oxymethyltetrazine (voTz) as an all-in-one reagent for modular preparation of tetrazine-caged prodrugs and chemoselective labeling of peptides to produce bioorthogonal activable peptide-prodrug conjugates.

  • Xinyu He
  • , Jie Li
  •  & Haoxing Wu

• Article
  28 March 2024 | Open Access

  Bioorthogonal photocatalytic proximity labeling in primary living samples

  Studying subcellular proteomes in primary living cells is crucial for understanding health and disease. Here, the authors introduce CAT-S, a non-genetic method based on photocatalysis, enabling in situ deciphering of mitochondrial proteomes in primary cells from mouse tissues and human blood.

  • Ziqi Liu
  • , Fuhu Guo
  •  & Xinyuan Fan

• Article
  19 March 2024 | Open Access

  2H-Thiopyran-2-thione sulfine, a compound for converting H₂S to HSOH/H₂S₂ and increasing intracellular sulfane sulfur levels

  Reactive sulfane sulfur species such as persulfides and H₂S₂ are important redox regulators and linked to H₂S signaling, but their study is hindered by a lack of suitable donors to produce them. Here, the authors report 2H-thiopyran-2-thione sulfine (TTS), a compound which can specifically convert H₂S to HSOH, and then to H₂S₂ in the presence of excess H₂S.

  • Qi Cui
  • , Meg Shieh
  •  & Ming Xian

• Article
  29 February 2024 | Open Access

  OrthoID: profiling dynamic proteomes through time and space using mutually orthogonal chemical tools

  Proteomics at the organelle contact site remains challenging due to the spatial and temporal dynamics of proteins. Here, the authors developed OrthoID, a mutually orthogonal dual enzymatic proteomics approach to explore the proteome at the contact site of the endoplasmic reticulum and mitochondria.

  • Ara Lee
  • , Gihyun Sung
  •  & Kimoon Kim

• Article
  17 February 2024 | Open Access

  Spatiotemporal and direct capturing global substrates of lysine-modifying enzymes in living cells

  Here the authors report a strategy to directly capture substrates of lysine-modifying enzymes via post-translational modification (PTM)-acceptor residue crosslinking in living cells, enabling global profiling of substrates of PTM-enzymes and validation of PTM-sites in a straightforward manner.

  • Hao Hu
  • , Wei Hu
  •  & Xiao-Hua Chen

• Article
  09 February 2024 | Open Access

  Reaction engineering blocks ether cleavage for synthesizing chiral cyclic hemiacetals catalyzed by unspecific peroxygenase

  Hemiacetal compounds are valuable building blocks in synthetic chemistry, but difficult to obtain by enzymatic synthesis. Here, the authors use reaction engineering of an immobilized unspecific peroxygenase from Agrocybe aegerita for selective C-H bond oxyfunctionalisation of environmentally significant cyclic ethers to chiral cyclic hemiacetals.

  • Xiaofeng Han
  • , Fuqiang Chen
  •  & Wuyuan Zhang

• Article
  09 February 2024 | Open Access

  Using the heme peroxidase APEX2 to probe intracellular H₂O₂ flux and diffusion

  Previous genetically encoded H₂O₂ probes are based on reversible thiol oxidation. Here, a heme peroxidase is introduced as a thiol-independent H₂O₂ probe. APEX2 converts H₂O₂ into fluorescent or luminescent signals, allowing its quantification.

  • Mohammad Eid
  • , Uladzimir Barayeu
  •  & Tobias P. Dick

• Article
  02 February 2024 | Open Access

  Early onset diagnosis in Alzheimer’s disease patients via amyloid-β oligomers-sensing probe in cerebrospinal fluid

  In this work, the authors characterize a small molecule fluorescent probe pioneering early diagnosis of Alzheimer’s disease through identification of amyloid-β oligomers in patients’ cerebrospinal fluid, demonstrating potential for clinical application.

  • Jusung An
  • , Kyeonghwan Kim
  •  & Jong Seung Kim

• Article
  04 January 2024 | Open Access

  DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance

  Targeted protein degradation (TPD) is a key modality for drug discovery. Here the authors present the discovery and analysis of reversible DCAF1-PROTACs, which show efficacy in cellular environments resistant to VHL-PROTACs or with acquired resistance to CRBN-PROTACs.

  • Martin Schröder
  • , Martin Renatus
  •  & Claudio R. Thoma

• Article
  09 December 2023 | Open Access

  Harnessing PROTAC technology to combat stress hormone receptor activation

  Stress-hormone receptors are important therapeutic targets for many diseases but the currently clinically approved inhibitor lacks specificity. Here the authors present a stress hormone receptor depletion tool that differs in its mode of action making it specific in counteracting the effects of stress.

  • Mahshid Gazorpak
  • , Karina M. Hugentobler
  •  & Katharina Gapp

• Article
  01 December 2023 | Open Access

  A simple method for developing lysine targeted covalent protein reagents

  The combination of a covalent electrophile with a peptide or protein-based scaffold enables the targeting of shallow protein surfaces, but the approaches to convert native peptide sequences into covalent binders are missing. Here, the authors report the design of protein-based thiomethacrylate ester electrophiles that can be installed on unprotected peptides and proteins via cysteine side chains and react efficiently and selectively with cysteine and lysine side chains on the target.

  • Ronen Gabizon
  • , Barr Tivon
  •  & Nir London

• Article
  01 November 2023 | Open Access

  Recognition and reprogramming of E3 ubiquitin ligase surfaces by α-helical peptides

  Identification of molecules that induce novel interactions between proteins has been limited by the complexity of rationally designing interactions. The authors report a method to discover molecular glue-like “trimerizers” based on α-helically constrained peptides that can co-opt the surfaces of E3 ubiquitin ligases to bind therapeutically important proteins.

  • Olena S. Tokareva
  • , Kunhua Li
  •  & John H. McGee

• Article
  17 October 2023 | Open Access

  Capturing nascent extracellular vesicles by metabolic glycan labeling-assisted microfluidics

  Temporally sorting EV populations is hard. Here the authors report a microfluidic-based strategy to enable selective isolation of nascent EVs by using azido groups to act as a timestamp for click chemistry labelling: they apply this to mouse models of anti-PD-L1 immunotherapy.

  • Qiuyue Wu
  • , Wencheng Wang
  •  & Yanling Song

• Article
  10 October 2023 | Open Access

  Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2

  SH2 domains are challenging to target using small molecules. Here, the authors develop phosphotyrosine-based covalent ligands of the E3 ligase SOCS2 using structure-based design. A pro-drug approach yields cell active inhibitors that block SOCS2 substrate recruitment.

  • Sarath Ramachandran
  • , Nikolai Makukhin
  •  & Alessio Ciulli

• Article
  28 September 2023 | Open Access

  An amide to thioamide substitution improves the permeability and bioavailability of macrocyclic peptides

  Solvent shielding of the amide hydrogen bond donor through chemical modification or conformational control has been successfully utilized to impart membrane permeability to macrocyclic peptides. Here, the authors show that passive membrane permeability can also be conferred by masking the amide hydrogen bond acceptor through thioamide substitution, leading to improved pharmacological properties of peptide macrocycles.

  • Pritha Ghosh
  • , Nishant Raj
  •  & Jayanta Chatterjee

• Article
  06 September 2023 | Open Access

  A cytotoxic T cell inspired oncolytic nanosystem promotes lytic cell death by lipid peroxidation and elicits antitumor immune responses

  Different types of lytic cell death can trigger an anti-tumor immune response. Here the authors report the design of a near infrared light controllable micron-scale oncolytic system, triggering lipid peroxidation and lytic cell death in tumors as well anti-tumor immunity in preclinical cancer models.

  • Zhigui Zuo
  • , Hao Yin
  •  & Qinyang Wang

• Article
  23 August 2023 | Open Access

  Click-electrochemistry for the rapid labeling of virus, bacteria and cell surfaces

  Methods for direct covalent ligation of microorganism surfaces are scarce. Here, the authors developed a rapid electrochemical process for the direct covalent ligation and labelling of the surfaces of virus, bacteria and cells using N-methylluminol, a fully tyrosine-selective protein anchoring group.

  • Sébastien Depienne
  • , Mohammed Bouzelha
  •  & Sébastien G. Gouin

• Article
  12 July 2023 | Open Access

  Deciphering intercellular signaling complexes by interaction-guided chemical proteomics

  Systematic profiling of the indirect cell–cell interactions remains challenging. Here, the authors report a chemical proteomics method to identify ligand-receptor complexes formed between cell surface receptors and secreted proteins from neighboring cells.

  • Jiangnan Zheng
  • , Zhendong Zheng
  •  & Ruijun Tian

• Article
  10 July 2023 | Open Access

  Bioinspired one-pot furan-thiol-amine multicomponent reaction for making heterocycles and its applications

  Homogeneous engineering of proteins is promising to study biological functions and for the development of therapeutic conjugates. Here, the authors report a one-pot multicomponent Furan-Thiol-Amine reaction for diverse applications, including labelling of peptides, synthesis of macrocyclic and stapled peptides, selective modification of different proteins with varying payloads, and labelling of lysine and cysteine in a complex human proteome.

  • Yuwen Wang
  • , Patrick Czabala
  •  & Monika Raj

• Article
  05 July 2023 | Open Access

  Modular synthesis of clickable peptides via late-stage maleimidation on C(7)-H tryptophan

  Cyclic peptides are of interest due to their application in pharmaceutical industry, but currently there are limited methodologies for their synthesis. Here, the authors report an efficient and direct peptide cyclization via rhodium(III)-catalysed C(7)-H maleimidation.

  • Peng Wang
  • , Jiang Liu
  •  & Yuguo Zheng

• Article
  05 July 2023 | Open Access

  Direct mapping of kidney function by DCE-MRI urography using a tetrazinanone organic radical contrast agent

  Current clinical methods for assessing kidney function report an aggregate value for both kidneys, and lack the ability to say which kidney is dysfunctioning or even to localize the dysfunction to a region of renal pathology. Here, the authors show that an injectable dye can be used to map kidney function by magnetic resonance imaging, offering a safer alternative than existing dyes for the spatial evaluation of kidney health.

  • Nicholas D. Calvert
  • , Alexia Kirby
  •  & Adam J. Shuhendler

• Article
  15 June 2023 | Open Access

  N-Acryloylindole-alkyne (NAIA) enables imaging and profiling new ligandable cysteines and oxidized thiols by chemoproteomics

  Cysteine is a popular target of covalent drugs and can undergo redox modifications. Here, the authors developed cysteine probes, N-acryloylindole-alkynes, for imaging and chemoproteomics to study cysteine oxidation and to identify targetable hotspots by small molecule compounds.

  • Tin-Yan Koo
  • , Hinyuk Lai
  •  & Clive Yik-Sham Chung

• Article
  09 June 2023 | Open Access

  Systematic detection of tertiary structural modules in large RNAs and RNP interfaces by Tb-seq

  Compact RNA structural motifs control many aspects of gene expression, but methods for their identification are lacking. Here the authors present a sequencing-based terbium probing approach to detect complex 3D structural elements, which can be used to pinpoint potential riboregulatory elements.

  • Shivali Patel
  • , Alec N. Sexton
  •  & Anna Marie Pyle

• Article
  08 June 2023 | Open Access

  THRONCAT: metabolic labeling of newly synthesized proteins using a bioorthogonal threonine analog

  Incorporating bioorthogonally-modified amino acids into newly synthesized proteins allows studying the nascent proteome, but current methods often require special conditions or are toxic to cells. Here, the authors develop a method that uses β-ethynylserine to label nascent proteins under standard conditions without harming cells.

  • Bob J. Ignacio
  • , Jelmer Dijkstra
  •  & Kimberly M. Bonger

• Article
  03 June 2023 | Open Access

  Systematic literature review reveals suboptimal use of chemical probes in cell-based biomedical research

  Chemical probes and their correct use are essential for accurate and robust data. Here, authors show that only 4% of analyzed publications used chemical probes in line with recommendations. This indicates that the best practice with chemical probes is yet to be implemented in research.

  • Jayden Sterling
  • , Jennifer R. Baker
  •  & Lenka Munoz

• Article
  23 May 2023 | Open Access

  Genetically encoded photocatalytic protein labeling enables spatially-resolved profiling of intracellular proteome

  Mapping the subcellular organization of proteins is crucial for understanding their biological functions. Here, the authors develop a genetically encoded photocatalytic labeling method for profiling the subcellular proteome in multiple organelles.

  • Fu Zheng
  • , Chenxin Yu
  •  & Peng Zou

• Article
  25 March 2023 | Open Access

  Neutron-encoded diubiquitins to profile linkage selectivity of deubiquitinating enzymes

  Most insights into deubiquitinase (DUB) substrate specificity originate from studies with isolated di-ubiquitins (diUb), but in cells diUbs with different linkage types coexist. Here, the authors develop a mass spectrometric DUB activity assay that can probe all diUbs simultaneously under substrate competition conditions.

  • Bianca D. M. van Tol
  • , Bjorn R. van Doodewaerd
  •  & Paul P. Geurink

• Article
  24 March 2023 | Open Access

  Small molecule-nanobody conjugate induced proximity controls intracellular processes and modulates endogenous unligandable targets

  Induced proximity can be used to control diverse cellular processes. Here, the authors develop nanobody-based proximity inducers called SNACIPs, which can be used to regulate either tagged or endogenous proteins, and demonstrate their use in blocking microtubule nucleation for tumour growth inhibition in vivo.

  • Xiaofeng Sun
  • , Chengjian Zhou
  •  & Xi Chen

• Article
  24 March 2023 | Open Access

  Transmembrane signaling by a synthetic receptor in artificial cells

  Transmembrane signaling is the core adaptation in nature that allows cells to communicate. Here, the authors engineer signaling through the lipid bilayer using chemical, synthetic receptors for their use in the design of artificial cells.

  • Ane Bretschneider Søgaard
  • , Andreas Bøtker Pedersen
  •  & Alexander N. Zelikin

• Article
  09 March 2023 | Open Access

  A general highly efficient synthesis of biocompatible rhodamine dyes and probes for live-cell multicolor nanoscopy

  Rhodamines are privileged fluorescent dyes for labelling intracellular structures in living cells. Here, the authors present a facile protecting-group-free synthesis permitting generation of a wide range of symmetrical and unsymmetrical 4-carboxyrhodamines covering the whole visible spectrum.

  • Jonas Bucevičius
  • , Rūta Gerasimaitė
  •  & Gražvydas Lukinavičius

• Article
  20 February 2023 | Open Access

  Identification of global inhibitors of cellular glycosylation

  Here, the authors discover small molecules that inhibit glycosylation processes that occur in the Golgi apparatus of cells. The molecules reversibly inhibit formation of elaborate glycan structures without affecting secretion of glycoproteins.

  • Daniel Madriz Sørensen
  • , Christian Büll
  •  & Yoshiki Narimatsu

• Article
  08 February 2023 | Open Access

  Accelerating inhibitor discovery for deubiquitinating enzymes

  Deubiquitinases (DUBs) are key signaling enzymes, many of which lack selective inhibitors. Chan et al. pair a DUB-focused covalent library to mass spectrometry activity-based protein profiling, leading to selective hits against 23 endogenous DUBs and a first-in-class VCPIP1 probe with nanomolar potency.

  • Wai Cheung Chan
  • , Xiaoxi Liu
  •  & Sara J. Buhrlage

• Article
  18 January 2023 | Open Access

  Revealing the tissue-level complexity of endogenous glucagon-like peptide-1 receptor expression and signaling

  Visualizing endogenous GPCRs is challenging. Here the authors generate mice with an enzyme self-label genome-edited into the endogenous glucagon-like peptide-1 receptor locus, design fluorescent dyes for specific labelling in complex tissue, and reveal tissue-level organisation and dynamics of an endogenous class B GPCR.

  • Julia Ast
  • , Daniela Nasteska
  •  & David J. Hodson

• Article
  14 November 2022 | Open Access

  A fluorogenic probe for predicting treatment response in non-small cell lung cancer with EGFR-activating mutations

  The presence of activating epidermal growth factor receptor (EGFR) mutations in patients with lung cancer correlates to improved response to EGFR-tyrosine kinase inhibitors. Here, the authors present a fluorescence-activated cell sorting assay to identify EGFR mutations with functional activity in patients and demonstrate its utility in predicting response to EGFR-TKI.

  • Hui Deng
  • , Qian Lei
  •  & Weimin Li

• Article
  05 November 2022 | Open Access

  A biomimetic electrostatic assistance for guiding and promoting N-terminal protein chemical modification

  Phosphorylation is a mechanism used by cells to promote proteins-biomolecules association. Here, the authors show the effect of the interactions between proteins equipped with positively charged arginines and peptides harbouring negatively charged phosphoserines, enabling rate acceleration and chemical processes in dilute conditions.

  • Nathalie Ollivier
  • , Magalie Sénéchal
  •  & Oleg Melnyk

• Article
  10 October 2022 | Open Access

  Structural basis for specific inhibition of the deubiquitinase UCHL1

  The deubiquitinase UCHL1 has been linked to cancer invasiveness and neurodegeneration yet its molecular roles have remained poorly defined. Here the authors reveal the structural basis for how UCHL1 can be specifically inhibited and how chemogenomic probes can be used to dissect its functions in living cells.

  • Christian Grethe
  • , Mirko Schmidt
  •  & Malte Gersch

• Article
  25 August 2022 | Open Access

  Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance

  The development of antimalarials against the human liver and asexual blood stages is one of the top public health challenges. Here, the authors report a single-step biochemical assay for the characterization of prolyl-tRNA synthetase inhibitors, and develop high-affinity inhibitors for the enzyme, including elusive triple-site ligands.

  • Mark A. Tye
  • , N. Connor Payne
  •  & Ralph Mazitschek

• Article
  24 August 2022 | Open Access

  Rational design of a sensitivity-enhanced tracer for discovering efficient APC–Asef inhibitors

  The adenomatous polyposis coli (APC)–Asef protein interaction is essential for colorectal cancer metastasis. Here, the authors present the rational design of a sensitivity-enhanced tracer for fluorescence polarization assays, enabling them to discover more efficient APC–Asef interaction inhibitors.

  • Jie Zhong
  • , Yuegui Guo
  •  & Jian Zhang

• Article
  29 July 2022 | Open Access

  Defunctionalizing intracellular organelles such as mitochondria and peroxisomes with engineered phospholipase A/acyltransferases

  Approaches for manipulating individual organelles are important for learning more about their functions. Here the authors report a tool utilising phospholipase A/acyltransferases (PLAATs) for rapid defunctionalisation of organelles through remodelling of the membrane phospholipids.

  • Satoshi Watanabe
  • , Yuta Nihongaki
  •  & Takanari Inoue

• Article
  14 July 2022 | Open Access

  Breaking photoswitch activation depth limit using ionising radiation stimuli adapted to clinical application

  Triggered therapeutics are of interest but currently suffer from limited penetration depth of light sources. Here, the authors report on the development of a system, called radioswitch, that uses ionising irradiation to switch an azobenzene modified drug to an active form for deep tissue triggered therapeutic application.

  • Alban Guesdon-Vennerie
  • , Patrick Couvreur
  •  & Guillaume Bort

• Article
  08 July 2022 | Open Access

  A luciferase prosubstrate and a red bioluminescent calcium indicator for imaging neuronal activity in mice

  Bioluminescence imaging of neuronal activity is desired. Here the authors report a luciferase prosubstrate activatable in vivo by nonspecific esterase and engineer a bioluminescent indicator with responsiveness to calcium ions: integration of these components enabled imaging of neuronal activity in mice.

  • Xiaodong Tian
  • , Yiyu Zhang
  •  & Hui-Wang Ai

• Article
  23 June 2022 | Open Access

  Macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR

  Mutations in the chloride channel CFTR that impair plasma membrane insertion and ion transport are the cause of cystic fibrosis. Here, the authors identify a macrocycle that stabilizes the interaction of mutant CFTR with the chaperone-like protein 14-3-3 and rescues its biological function.

  • Loes M. Stevers
  • , Madita Wolter
  •  & Christian Ottmann

• Article
  18 June 2022 | Open Access

  Bioorthogonally activatable cyanine dye with torsion-induced disaggregation for in vivo tumor imaging

  Expanding the responsive dyes repertoire is currently a developing field in biorthogonal chemistry. In this article, the authors develop fluorophores that turn on their near-infrared fluorescence upon biorthogonal reaction based on a “torsion-induced disaggregation” approach, allowing for sensitive in vivo imaging of tumors.

  • Xianghan Zhang
  • , Jingkai Gao
  •  & Zhongliang Wang

• Article
  11 June 2022 | Open Access

  Photoredox catalytic radical fluorosulfonylation of olefins enabled by a bench-stable redox-active fluorosulfonyl radical precursor

  Sulfonyl fluorides are compounds with potential application in chemical biology and drug discovery, but their preparation can be challenging. Here, the authors present a type of bench-stable fluorosulfonyl radical reagents that enable radical fluorosulfonylation reactions via photoredox catalysis.

  • Peng Wang
  • , Honghai Zhang
  •  & Saihu Liao

• Article
  12 May 2022 | Open Access

  Dual-resolving of positional and geometric isomers of C=C bonds via bifunctional photocycloaddition-photoisomerization reaction system

  The simultaneous identification of position and configuration of double bonds in unsaturated lipids is challenging. Here, the authors develop a workflow for deep structural lipidomics to address this issue using a bifunctional reaction system combined with liquid chromatography-mass spectrometry, revealing double bond patterns in bacteria and in mouse brain ischemia.

  • Guifang Feng
  • , Ming Gao
  •  & Suming Chen

• Article
  09 May 2022 | Open Access

  A negative-solvatochromic fluorescent probe for visualizing intracellular distributions of fatty acid metabolites

  Metabolic distribution of fatty acids to organelles is an essential biological process for energy homeostasis. Here the authors report a fluorescent probe that allows multicolour visualisation of the intracellular distribution of exogenous fatty acids, metabolically incorporated as lipid components.

  • Keiji Kajiwara
  • , Hiroshi Osaki
  •  & Masayasu Taki

• Article
  02 May 2022 | Open Access

  A fluorogenic probe for granzyme B enables in-biopsy evaluation and screening of response to anticancer immunotherapies

  Granzyme B is found in activated T cells and can be used as a marker of T cell activation. Here, the authors generate a fluorescent probe that can detect Granzyme B levels in tumours, and has the potential to be used as a biomarker of response to immunotherapy.

  • Jamie I. Scott
  • , Lorena Mendive-Tapia
  •  & Marc Vendrell

• Article
  25 April 2022 | Open Access

  Ratiometric afterglow luminescent nanoplatform enables reliable quantification and molecular imaging

  Afterglow luminescence is promising for non-background molecular imaging in vivo. Here the authors report a ratiometric afterglow luminescent nanoplatform to generate activatable afterglow probes for quantification of specific analytes including NO.

  • Yongchao Liu
  • , Lili Teng
  •  & Weihong Tan

• Article
  01 April 2022 | Open Access

  Cyclic 5-membered disulfides are not selective substrates of thioredoxin reductase, but are opened nonspecifically

  Cyclic five-membered disulfides (1,2-dithiolanes) have been reported either as nonspecific redox motifs, or as highly specific cellular probes for thioredoxin reductase (TrxR). Here the authors show that 1,2-dithiolane probes are nonspecifically reduced by a range of thiol reductants and are not sensitive to TrxR modulation, thus they are unsuitable as cellular probes for TrxR.

  • Jan G. Felber
  • , Lena Poczka
  •  & Oliver Thorn-Seshold

• Article
  18 March 2022 | Open Access

  Characterization of protein unfolding by fast cross-linking mass spectrometry using di-ortho-phthalaldehyde cross-linkers

  Conformations sampled by a protein while it unfolds are difficult to visualize. Here, the authors develop di-ortho-phthalaldehyde cross-linkers for rapid chemical cross-linking mass spectrometry analysis and demonstrate that this method captures the conformations of protein unfolding intermediates.

  • Jian-Hua Wang
  • , Yu-Liang Tang
  •  & Xiaoguang Lei