Chemical tools

  • Article
    | Open Access

    The mechanism-of-action of many electrohilic drugs remains poorly understood. Here, the authors use a redox-targeting approach to elucidate the basis for the innate immune cell toxicity of dimethyl fumarate, showing that it modifies Keap1 to trigger mitochondrial-targeted neutrophil/macrophage apoptosis.

    • Jesse R. Poganik
    • , Kuan-Ting Huang
    •  & Yimon Aye
  • Article
    | Open Access

    Elucidating specific effects of protein kinase Akt isoforms remains challenging. Here, the authors establish an Akt isoform-dependent cellular model system and use it, together with X-ray crystallography and structure-based ligand design, to develop isoform-selective covalent-allosteric Akt inhibitors

    • Lena Quambusch
    • , Laura Depta
    •  & Daniel Rauh
  • Article
    | Open Access

    Here, the authors show structural, biochemical, and functional insights into the discovery of epichaperome‐ directed chemical probes for use in central nervous system diseases. Probes emerging from this work have translated to human clinical studies in Alzheimer’s disease and cancer.

    • Alexander Bolaender
    • , Danuta Zatorska
    •  & Gabriela Chiosis
  • Article
    | Open Access

    PARG and ARH3 are the main hydrolases to reverse serine poly(ADP-ribosylation) yet their activities in the process differ. Here, the authors synthesise linear and branched poly(ADP-ribose) molecules, perform structure-function analysis and elucidate the mechanistic differences between PARG and ARH3.

    • Johannes Gregor Matthias Rack
    • , Qiang Liu
    •  & Ivan Ahel
  • Article
    | Open Access

    The authors develop a method to build Manhattan Raman Scattering (MARS) probes based on different core atoms, conjugation ring numbers, and stable isotope substitutions. A quantitative model predicts vibrational frequencies of MARS dyes from structures, which are used in supermultiplexed vibrational imaging.

    • Yupeng Miao
    • , Naixin Qian
    •  & Wei Min
  • Article
    | Open Access

    Despite considerable efforts, quantitative prediction of various molecular properties remains a challenge. Here, the authors propose an algebraic graph-assisted bidirectional transformer, which can incorporate massive unlabeled molecular data into molecular representations via a self-supervised learning strategy and assisted with 3D stereochemical information from graphs.

    • Dong Chen
    • , Kaifu Gao
    •  & Feng Pan
  • Article
    | Open Access

    Self-assembling peptides (SAPs) can be used to build biomaterials, but genetically encoded SAPs have rarely been used as building blocks in cells. Here, the authors design a SAP that can be genetically fused to target proteins to induce their intracellular clustering and modulate their signaling functions.

    • Takayuki Miki
    • , Taichi Nakai
    •  & Hisakazu Mihara
  • Article
    | Open Access

    The circadian clock is an internal mechanism that controls various physiological processes, such as the sleep-wake cycle, but its precise regulation is challenging. Here, the authors develop a visible light-responsive inhibitor of casein kinase I which controls the period and phase of cellular and tissue circadian rhythms in a reversible manner.

    • Dušan Kolarski
    • , Carla Miró-Vinyals
    •  & Ben L. Feringa
  • Article
    | Open Access

    The ER chaperone BiP is critical for the unfolded protein response and tightly regulated through reversible AMPylation by FICD, but the structural basis is unknown. Here the authors use thiol-reactive nucleotide derivatives to stabilize the transient FICD:BiP complex and determine its crystal structure.

    • Joel Fauser
    • , Burak Gulen
    •  & Aymelt Itzen
  • Article
    | Open Access

    Metabolites can distinguish pathogenic from healthy cells, but they are hard to couple to current photosensitizers without altering their biological activity. Here the authors design a new family of photosensitizers that retain metabolite function to target pathogenic cells and ablate them by photodynamic therapy.

    • Sam Benson
    • , Fabio de Moliner
    •  & Marc Vendrell
  • Article
    | Open Access

    Monitoring the activity of the processive motor protein kinesin-1 in live cells is currently difficult. Here the authors report the fluorogenic small molecule QPD-OTf, a kinesin-1 substrate that causes activity-dependent dye precipitation.

    • Simona Angerani
    • , Eric Lindberg
    •  & Nicolas Winssinger
  • Article
    | Open Access

    The connection between metal binding to proteins and availabilities of different metals in cells has been unclear. Here, the authors report a metalation-calculator that takes into account competition between metals and their variable accessibility, and thereby elucidate in vivo metal occupancies of three different proteins, CobW, YeiR and YjiA.

    • Tessa R. Young
    • , Maria Alessandra Martini
    •  & Nigel J. Robinson
  • Article
    | Open Access

    Hundreds of BRAF mutations have been identified in patients with cancer but currently approved drugs only target BRAF V600 mutants. Here, the authors develop a vemurafenib-based PROTAC that induces degradation of all classes of BRAF mutants without affecting wild-type RAF proteins.

    • Shanique Alabi
    • , Saul Jaime-Figueroa
    •  & Craig M. Crews
  • Article
    | Open Access

    The analysis of AMPA-type glutamate receptor (AMPAR) trafficking is essential for understanding molecular mechanisms of learning and memory, but the analytical tools are currently limited. Here, the authors report a method that combines affinity-based receptor labeling and bioorthogonal click chemistry to quantify AMPAR distribution and trafficking under physiological conditions.

    • Kento Ojima
    • , Kazuki Shiraiwa
    •  & Shigeki Kiyonaka
  • Article
    | Open Access

    Mitochondrial oxidation-induced cell death is an important physiological process activated by cancer therapeutics, but its investigation is challenging. Here, the authors report a multifunctional iridium(III) photosensitiser, Ir-OA, able to induce mitochondrial oxidative stress and monitor the corresponding changes in mitochondrial properties.

    • Chaiheon Lee
    • , Jung Seung Nam
    •  & Tae-Hyuk Kwon
  • Article
    | Open Access

    ADP-ribosylated peptides are important molecular tools, however, the lack of effective synthetic methods hinders the access to their complex structures. Here, the authors present a biomimetic α-selective ribosylation reaction coupled with click chemistry ultimately providing a two-step modular synthesis of α-ADP-ribosylated peptides.

    • Anlian Zhu
    • , Xin Li
    •  & Lingjun Li
  • Article
    | Open Access

    Developing new click chemistry reactions for robust molecular assembly remains challenging. Here the authors report a light-induced primary amines and o-nitrobenzyl alcohols photoclick cyclization for rapid and modular functionalization of small molecules and native biomolecules, in vitro and in living systems.

    • An-Di Guo
    • , Dan Wei
    •  & Xiao-Hua Chen
  • Article
    | Open Access

    The dTAG system is used to rapidly deplete tagged target proteins in vitro and in vivo, but there are context- and protein-specific differences in its effectiveness. Here, the authors develop a second generation dTAG molecule that can degrade previously recalcitrant target proteins in cells and mice.

    • Behnam Nabet
    • , Fleur M. Ferguson
    •  & Nathanael S. Gray
  • Article
    | Open Access

    Light-based modulation of the microtubule (MT) cytoskeleton is an attractive goal for spatiotemporally-resolved MT studies. Here the authors develop a first generation photoswitchable small molecule MT stabiliser based on paclitaxel, allowing optical control over cellular MT dynamics.

    • Adrian Müller-Deku
    • , Joyce C. M. Meiring
    •  & Oliver Thorn-Seshold
  • Article
    | Open Access

    Cas9 fusions partners are often limited to natural polypeptide chains at the Cas9 termni. Here the authors present a platform for site-specific and multiple-site conjugation to both termini and internal sites of Cas9, and they apply this platform to efficiently engineer insulin-producing β cells.

    • Donghyun Lim
    • , Vedagopuram Sreekanth
    •  & Amit Choudhary
  • Article
    | Open Access

    The mechanism underlying the cellular entry of Zika virus is not fully understood. Here, the authors use a chemically modified virus and time-resolved proteomics to capture interacting host proteins during virus entry and identify NCAM1 as a ZIKV receptor.

    • Mayank Srivastava
    • , Ying Zhang
    •  & W. Andy Tao
  • Article
    | Open Access

    Targeted protein degradation is an attractive therapeutic strategy to deplete oncogenic proteins in tumours. Here the authors demonstrate the specific targeting of endogenous KRAS protein for degradation from cancer cells, and regression of tumours expressing mutant KRAS in a mouse model.

    • Nicolas Bery
    • , Ami Miller
    •  & Terry Rabbitts
  • Article
    | Open Access

    Chemical tools to monitor drug-target engagement of endogenous enzymes are essential for preclinical target validation. Here, the authors present a chemical genetics strategy to study target engagement of endogenous kinases, achieving specific labeling and inactivation of FES kinase to provide insights into FES’ role in neutrophil phagocytosis.

    • Tom van der Wel
    • , Riet Hilhorst
    •  & Mario van der Stelt
  • Article
    | Open Access

    Formaldehyde (FA) is a popular cross-linking reagent, but applying it for cross-linking mass spectrometry (XLMS) has been largely unsuccessful. Here, the authors show that cross-links in structured proteins are the product of two FA molecules and identify hundreds of FA cross-links by XLMS in vitro and in situ.

    • Tamar Tayri-Wilk
    • , Moriya Slavin
    •  & Nir Kalisman
  • Article
    | Open Access

    Sequestration of reactants in lipid vesicles is a strategy prevalent in biological systems to raise the rate and specificity of chemical reactions. Here, the authors show that micelle-assisted reactions facilitate native chemical ligation between a peptide-thioester and a Cys-peptide modified by a lipid-like moiety.

    • Shuaijiang Jin
    • , Roberto J. Brea
    •  & Neal K. Devaraj
  • Article
    | Open Access

    Granadaene, produced by Group B Streptococcus (GBS), is a long polyene lipid involved in cellular toxicity and hemolytic activity. Here, the authors synthesize and characterize granadaene-like compounds and show that a non-toxic analog diminishes GBS infection in mice when incorporated into a vaccine formulation.

    • Blair Armistead
    • , Pilar Herrero-Foncubierta
    •  & Lakshmi Rajagopal
  • Article
    | Open Access

    Optogenetic manipulation of protein localisation in cells involves the creation of fusions that can influence activity. Here the authors develop a near-infrared light-responsive aptamer-based system to regulate the nuclear-cytoplasmic shuttling of NF-κB subunit RelA.

    • Sitao Xie
    • , Yulin Du
    •  & Weihong Tan
  • Article
    | Open Access

    Glucagon-like peptide-1 receptor is an important regulator of appetite and glucose homeostasis. Here the authors describe super-resolution microscopy and in vivo imaging compatible fluorescent probes, which reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics in islets and brain.

    • Julia Ast
    • , Anastasia Arvaniti
    •  & David J. Hodson
  • Article
    | Open Access

    Targeted manipulations of neural activity in the living brain remain a significant challenge. In this study the authors introduce a paramagnetic analog of the drug muscimol that enables targeted neural inactivation to be performed with feedback from magnetic resonance imaging

    • Sarah Bricault
    • , Ali Barandov
    •  & Alan Jasanoff
  • Article
    | Open Access

    PRDM9 is a PR domain containing histone methyl transferase which expression is normally restricted to the germline that has also been linked to a number of somatic cancers. Here the authors describe the identification of a small molecule that selectivity inhibits the methyltransferase activity of PRDM9 in biochemical and cellular assays

    • Abdellah Allali-Hassani
    • , Magdalena M. Szewczyk
    •  & Masoud Vedadi
  • Article
    | Open Access

    Developing inhibitors that target specific protein-protein interactions (PPIs) is challenging. Here, the authors show that target selectivity and PPI blocking can be achieved simultaneously with PPI inhibitors that contain two functional modules, and create a paralog-selective PSD-95 inhibitor as proof-of-concept.

    • Charlotte Rimbault
    • , Kashyap Maruthi
    •  & Matthieu Sainlos
  • Article
    | Open Access

    Reliable methods of measuring intracellular H2O2 fluctuations are necessary to advance redox biology. Here the authors design a H2O2 sensor based on the fission yeast peroxiredoxin Tpx1 to sense nanomolar fluctuations of intracellular H2O2 in response to genetic and environmental perturbations.

    • Mercè Carmona
    • , Laura de Cubas
    •  & Elena Hidalgo
  • Article
    | Open Access

    Per-O-acetylated unnatural monosaccharides are popular tools for glycan labeling in live cells but can undergo unwanted side reactions with cysteines. Here, the authors develop unnatural sugars in a partially esterified form that are inert towards cysteines, and use them to probe O-GlcNAcylation in mESCs.

    • Yi Hao
    • , Xinqi Fan
    •  & Xing Chen
  • Article
    | Open Access

    Single-site labelling of proteins is desirable, e.g., for analytical purposes. Here, the authors developed a method in which they use an aldol-type reaction to modify proteins at N-terminal glycine residues in an efficient and selective manner, which is also applicable to cell lysates.

    • Landa Purushottam
    • , Srinivasa Rao Adusumalli
    •  & Vishal Rai
  • Article
    | Open Access

    Ceramides are lipids that act directly on mitochondria to trigger apoptosis, but the underlying mechanism remains largely unclear. Here authors use a photoactivatable ceramide probe combined with a computation approach and functional studies to identify the voltage-dependent anion channel VDAC2 as a direct effector of ceramide-mediated cell death.

    • Shashank Dadsena
    • , Svenja Bockelmann
    •  & Joost C. M. Holthuis
  • Article
    | Open Access

    Super-resolution microscopy with spontaneously blinking dyes is dependent on pH and polarity of the medium. Here the authors introduce a photoactivatable fluxional fluorophore for live cell imaging that allows control over the fraction of spontaneously blinking molecules independently of medium properties.

    • Elias A. Halabi
    • , Dorothea Pinotsi
    •  & Pablo Rivera-Fuentes
  • Article
    | Open Access

    Two-photon absorption capacity of azobenzene photoswitches usually comes with a reduction in thermal stability. Here, the authors developed photoswitches with high two-photon sensitivity and enhanced cis isomer thermal lifetime for the control of glutamate receptors.

    • Gisela Cabré
    • , Aida Garrido-Charles
    •  & Ramon Alibés