Small molecules

  • Article
    | Open Access

    A major question in redox signaling is how H2O2 oxidizes target protein thiols in the presence of glutathione peroxidases and peroxiredoxins. We reveal signaling by H2O2 via its enzymatic conversion to an alkyl hydroperoxide that stereo-specifically escapes peroxidases and oxidizes target proteins.

    • Raphael F. Queiroz
    • , Christopher P. Stanley
    •  & Roland Stocker
  • Article
    | Open Access

    The human 2-oxoglutarate (2OG) oxygenases FIH and AspH are relevant drug targets. Here, the authors show that synthetic and naturally occurring 2OG derivatives can selectively modulate FIH and AspH activities, suggesting that these compounds may serve as a basis to develop 2OG oxygenase-targeting probes and drugs.

    • Yu Nakashima
    • , Lennart Brewitz
    •  & Christopher J. Schofield
  • Article
    | Open Access

    Humans are exposed to millions of chemicals but mass spectrometry (MS)-based targeted biomonitoring assays are usually limited to a few hundred known hazards. Here, the authors develop a workflow for MS-based untargeted exposome profiling of known and unidentified environmental chemicals.

    • Xin Hu
    • , Douglas I. Walker
    •  & Dean P. Jones
  • Article
    | Open Access

    Toll-like receptor 8 (TLR8) plays essential roles in the innate immune response to viral single-stranded RNA (ssRNA), so small molecule modulators of TLR8 are of interest, however adverse effects limit their use. Here, the authors report a tetrasubstituted imidazole CU-CPD107 with dichotomous behaviour, which inhibits R848-induced TLR8 signaling, but shows synergistic activity in the presence of ssRNA, making it a potential antiviral agent.

    • Yi Yang
    • , Adam Csakai
    •  & Hang Yin
  • Article
    | Open Access

    Synchronizing gene expression across eukaryotic communities presents complex challenges. Here the authors construct a compact synthetic system inspired by bacteria response to antibiotics that robustly converts chemical rhythms into synchronized gene expression across populations.

    • Sara Pérez-García
    • , Mario García-Navarrete
    •  & Krzysztof Wabnik
  • Article
    | Open Access

    Amyloid aggregation of mutant p53 contributes to its loss of tumor suppressor function and oncogenic gain-of-function. Here, the authors use a protein mimetic to abrogate mutant p53 aggregation and rescue p53 function, which inhibits cancer cell proliferation in vitro and halts tumor growth in vivo.

    • L. Palanikumar
    • , Laura Karpauskaite
    •  & Mazin Magzoub
  • Article
    | Open Access

    The histone methyltransferase ASH1L plays a role in various diseases, including cancer, and has been validated as a therapeutic target; however, no inhibitors of ASH1L have been reported. Here the authors present small molecule inhibitors of ASH1L and demonstrate their on-target activity in leukemia cells and a mouse model of leukemia.

    • David S. Rogawski
    • , Jing Deng
    •  & Jolanta Grembecka
  • Article
    | Open Access

    Carbon dots have attracted much attention for biomedical applications but potential degradation and associated toxicity are still poorly understood. Here, the authors report on a study into the photo-degradation of carbon dots, the products produced and associated cytotoxicity.

    • Yue-Yue Liu
    • , Nan-Yang Yu
    •  & Ai-Jun Miao
  • Article
    | Open Access

    Snakebite is a life-threatening neglected tropical disease that is currently treated using different antibody-based antivenoms, each effective against bites of specific snake species, but not others. Here, the authors show that a combination of two toxin-inhibiting repurposed drugs provides broad protection in experimental animals against the lethal effects of snakebites from multiple snake species.

    • Laura-Oana Albulescu
    • , Chunfang Xie
    •  & Nicholas R. Casewell
  • Article
    | Open Access

    ATP acts as a co-substrate in enzyme catalysed reactions, but can also specifically bind metal ions. Here, the authors show that ATP interacts with copper ions and forms a Cu(II)-ATP complex that efficiently catalyses Diels-Alder reactions, and determine ATP residues that are essential for this activity.

    • Changhao Wang
    • , Qianqian Qi
    •  & Jörg S. Hartig
  • 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

    FDA-approved RAF inhibitors poorly inhibit BRAF dimers, which limits their clinical efficacy in tumors expressing BRAFV600E mutant monomers. Here the authors identify FDA-approved Ponatinib as an effective inhibitor of BRAF monomers and dimers and designed PHI1, an inhibitor with a unique mode of action and selectivity for oncogenic BRAF dimers.

    • Xiomaris M. Cotto-Rios
    • , Bogos Agianian
    •  & Evripidis Gavathiotis
  • Article
    | Open Access

    Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of AML. Here, the authors report the molecular mechanisms by which NUP98-PHF23 recognizes the histone mark H3K4me3 and provide evidence of a direct link between the association of NUP98-PHD finger chimeras with H3K4me3-rich regions and leukemic transformation.

    • Yi Zhang
    • , Yiran Guo
    •  & Tatiana G. Kutateladze
  • Article
    | Open Access

    Inhibitors of the BET family proteins are limited by their potency and oral bio-availability. Here, the authors report a new BET inhibitor, NHWD-870, with improved potency compared to previous BET inhibitors, and show that it suppresses BRD4 and targets tumour associated macrophages.

    • Mingzhu Yin
    • , Ying Guo
    •  & Qin Yan
  • Article
    | Open Access

    Karrikins are germination stimulants perceived by KAI2 in Arabidopsis. Here the authors show that Brassica tournefortii, a close relative to Arabidopsis, has multiple copies of KAI2 with amino acid substitutions that confer responsiveness to the specific karrikin compounds found in wildfire smoke.

    • Yueming Kelly Sun
    • , Jiaren Yao
    •  & Mark T. Waters
  • Article
    | Open Access

    Sensitive diagnostic tools for bacterial infections of wounds and surgical sites are necessary to enable early detection and determine optimal means of treatment. Here, the authors develop a fluorescent and optoacoustic probe based on a maltotriose scaffold, which is selectively taken up by gram-positive and gram-negative bacteria.

    • Aimen Zlitni
    • , Gayatri Gowrishankar
    •  & Sanjiv Sam Gambhir
  • Article
    | Open Access

    Aspergillus fungi classified within the section Flavi include harmful and beneficial species. Here, Kjærbølling et al. analyse the genomes of 23 Flavi species, showing high genetic diversity and potential for synthesis of over 13,700 CAZymes and 1600 secondary metabolites.

    • Inge Kjærbølling
    • , Tammi Vesth
    •  & Mikael R. Andersen
  • Article
    | Open Access

    Small molecules in the rhizosphere regulate interactions between plants and other organisms. Here the authors show that an ascaroside pheromone secreted by plant-parasitic nematodes is converted by host plant peroxisomal β-oxidation into shorter side-chained ascarosides that repel nematodes.

    • Murli Manohar
    • , Francisco Tenjo-Castano
    •  & Frank C. Schroeder
  • Article
    | Open Access

    Damaged mitochondria are known to cause neuronal death, suggesting clearance as a potential therapy. Here, Moskal et al. show that ROCK inhibitors promote Parkin recruitment and mitophagy and have neuroprotective effects in fruit flies challenged with a toxin that induces mitochondrial damage.

    • Natalia Moskal
    • , Victoria Riccio
    •  & G. Angus McQuibban
  • Article
    | Open Access

    Targeted protein degradation (TPD) is a promising strategy for drug development. In this proof-of-concept study, the authors use telaprevir, which binds hepatitis C virus (HCV) NS3/4A protease, to target the protease for protein degradation, and show inhibition of wildtype as well as drug resistant HCV.

    • Mélissanne de Wispelaere
    • , Guangyan Du
    •  & Priscilla L. Yang
  • Article
    | Open Access

    RNA sensors—Riboswitches—respond to the binding of small molecules ligands through structure modification. Here the authors identify synthetic small molecules that bind and regulate the activity of PreQ1 Riboswitches despite having no obvious chemical similarity to the cognate ligand.

    • Colleen M. Connelly
    • , Tomoyuki Numata
    •  & John S. Schneekloth Jr.
  • Article
    | Open Access

    Protein kinase A (PKA) is typically activated by cAMP. Here, Bachmaier et al. show that PKA of Trypanosoma is activated by nucleoside-related ligands, explain the ligand selectivity swap by a co-crystal structure of trypanosome PKAR, and identify potential downstream targets by phosphoproteomics.

    • Sabine Bachmaier
    • , Yuri Volpato Santos
    •  & Michael Boshart
  • Article
    | Open Access

    Attempts to image activated macrophages in vivo have been hampered by selectivity and delivery problems. Here the authors develop a small molecule fluorescent probe specific to activated M1 and M2 macrophages, identify the orphan receptor Slc18b1/SLC18B1 as the mechanism of uptake, and use it to image atherosclerosis in mice.

    • Sung-Jin Park
    • , Beomsue Kim
    •  & Young-Tae Chang
  • Article
    | Open Access

    PROTACs enable targeted protein degradation by recruiting an E3 ligase to a specific substrate but the determinants of selectivity are not fully understood. Here, the authors show that varying the linker between warhead and E3 ligand and the orientation of the E3 ligase allow tuning PROTAC selectivity toward different p38 isoforms.

    • Blake E. Smith
    • , Stephen L. Wang
    •  & Craig M. Crews
  • Article
    | Open Access

    Clostridium difficile causes diarrhea and colitis by producing up to three different protein toxins. Here, Tam et al. show that an anthelmintic drug, niclosamide, inhibits the pathogenesis of all three toxins by targeting a host process required for toxin entry into host cells, without disrupting the gut microbiota.

    • John Tam
    • , Therwa Hamza
    •  & Roman A. Melnyk
  • Article
    | Open Access

    Rhabdopeptides are synthesized by non-ribosomal peptide synthetases (NRPSs) and the multiple NRPS subunits interact through docking domains (DD). Here the authors provide insights into DD interaction patterns and present the structures of three N-terminal docking domains (NDD) and a NDD-CDD complex and derive a set of recognition rules for DD interactions.

    • Carolin Hacker
    • , Xiaofeng Cai
    •  & Jens Wöhnert
  • Article
    | Open Access

    Targeting noncoding nucleic acids with small molecules represents an important and significant challenge in chemical biology and drug discovery. Here the authors characterize DC-34, a small molecule that exhibits selective binding to specific G4 structures, and provide a structural basis for its selectivity

    • David R. Calabrese
    • , Xiang Chen
    •  & John S. Schneekloth Jr.
  • Article
    | Open Access

    DNA is found in a dynamic equilibrium between standard Watson-Crick (WC) base pairs and non-standard Hoogsteen (HG) base pairs. Here the authors describe the influence of echinomycin and actinomycin D ligands binding on the HG-WC base pair dynamics in DNA.

    • Yu Xu
    • , James McSally
    •  & Hashim M. Al-Hashimi
  • Article
    | Open Access

    Gain-of-function mutants of p53 are important for cancer development and strategies to target specifically these isoforms are being investigated. Here the authors report that USP15 is a deubiquitinase specifically regulating p53-R175H levels that can be targeted by a small molecule.

    • Achuth Padmanabhan
    • , Nicholes Candelaria
    •  & JoAnne S. Richards
  • Article
    | Open Access

    There is growing evidence that the kinetics of interactions between inhibitors and their targets can strongly impact therapeutic efficacy. Here the authors describe an isothermal titration calorimetry-based method that can rapidly quantify inhibition kinetics and measure sub-nM binding affinities.

    • Justin M. Di Trani
    • , Stephane De Cesco
    •  & Anthony K. Mittermaier
  • Article
    | Open Access

    Plant pathogens translocate type III effector (T3E) proteins that may be recognized by plants to trigger immunity. Here, the authors show that the Xanthomonas T3E XopH possesses a novel 1-phytase activity that is required for XopH-mediated immunity of plants carrying the Bs7 resistance gene.

    • Doreen Blüher
    • , Debabrata Laha
    •  & Ulla Bonas
  • Article
    | Open Access

    Several families of natural compounds target core components of the pre-mRNA splicing machinery and display anti-tumor activity. Here the authors show that particular sequence features can be linked to drug response, and that drugs with very similar chemical structures display substantially different effects on splicing regulation.

    • Luisa Vigevani
    • , André Gohr
    •  & Juan Valcárcel
  • Article
    | Open Access

    Heteroatom-rich organoboron compounds are promising modulators of enzyme activity. Here, the authors report a library of aminocyanoboronates as serine hydrolases inhibitors with the most potent compound showing in vivo and in vitro nanomolar activity and high selectivity towards human ABHD3 hydrolase.

    • Joanne Tan
    • , Armand B. Cognetta III
    •  & Andrei K. Yudin
  • Article
    | Open Access

    Masitinib is a protein kinase inhibitor that sensitises refractory pancreatic adenocarcinoma cells to treatment with the nucleoside analog gemcitabine. Here the authors show that Masitinib activates deoxycytidine kinase to enhance phosphorylation of nucleoside analogue pro-drugs, increasing their potency.

    • Kahina Hammam
    • , Magali Saez-Ayala
    •  & Patrice Dubreuil