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| Open AccessEfflux pump-mediated resistance to antifungal compounds can be prevented by conjugation with triphenylphosphonium cation
Antifungal resistance due to upregulation of efflux pumps is common in Candida albicans. Here, the authors show that conjugation with mitochondria-targeting triphenylphosphonium cation can enhance or restore the antifungal activity of potential efflux pump substrates.
- Wenqiang Chang
- , Jun Liu
- & Hongxiang Lou
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Article
| Open AccessDesign of Peptoid-peptide Macrocycles to Inhibit the β-catenin TCF Interaction in Prostate Cancer
Small molecules and peptide inhibitors have their benefits and faults when it comes to inhibiting protein-protein interactions. Here, the authors designed a peptoid-peptide hybrid that inhibited β-catenin/TCF interactions, leading to inhibition of Wnt signalling in models of prostate cancer.
- Jeffrey A. Schneider
- , Timothy W. Craven
- & Susan K. Logan
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Article
| Open AccessMitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers
Several challenges are involved in direct targeting of mutant p53, while targeting altered fitness of cells with loss of wild type p53 is an alternative approach. Here they identify niclosamide to be selectively toxic to p53 deficient cells through a previously unknown mitochondrial uncoupling mechanism.
- R. Kumar
- , L. Coronel
- & C. F. Cheok
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Article
| Open AccessDirected evolution of CRISPR-Cas9 to increase its specificity
Undesired off-target effects can hamper the use of CRISPR-Cas9 in therapeutic applications. Here the authors use a directed evolution approach to develop Sniper-Cas9 which combines high specificity with no loss of on-target activity.
- Jungjoon K. Lee
- , Euihwan Jeong
- & Jin-Soo Kim
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| Open AccessRed blood cell-hitchhiking boosts delivery of nanocarriers to chosen organs by orders of magnitude
Unwanted uptake in the liver and limited accumulation in target organs is a major obstacle to targeted drug delivery. Here, the authors report on the hitchhiking of nanocarriers on red blood cells and the targeted upstream delivery to different target organs in mice, pigs and ex vivo human lungs.
- Jacob S. Brenner
- , Daniel C. Pan
- & Vladimir Muzykantov
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| Open AccessSpecific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity
Estrogen receptor alpha (ERα) plays critical roles in the etiology and treatment of breast cancer. Here the authors synthesize benzopyrans with variable side chains to identify antiestrogenic compounds and characterize OP-1074, a compound that exhibits pure antiestrogenic activity by inducing the degradation of ERα and possesses greater potency than tamoxifen or fulvestrant in a xenograft model.
- S. W. Fanning
- , L. Hodges-Gallagher
- & P. J. Kushner
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Article
| Open AccessTargeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome
Hutchinson-Gilford Progeria Syndrome is characterized by premature aging with cardiovascular disease being the main cause of death. Here the authors show that inhibition of the NAT10 enzyme enhances cardiac function and fitness, and reduces age-related phenotypes in a mouse model of premature aging.
- Gabriel Balmus
- , Delphine Larrieu
- & Stephen P. Jackson
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| Open AccessA DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
Activation of the tumor suppressor p53 is a promising approach in cancer therapy. Here, the authors discover a series of small molecule dihydroorotate dehydrogenase (DHODH) inhibitors that increase p53 synthesis and reduce tumor growth in synergy with the common mdm2 inhibitor nutlin3.
- Marcus J. G. W. Ladds
- , Ingeborg M. M. van Leeuwen
- & Sonia Laín
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Article
| Open AccessHarnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development
The activity of protein tyrosine phosphatase PTP1B, a major metabolic regulator, depends on its oxidation state. Here the authors identify and characterize a small molecule that targets the oxidized, inactive form of PTP1B, suggesting a new therapeutic approach to diabetes and obesity.
- Navasona Krishnan
- , Christopher A. Bonham
- & Nicholas K. Tonks
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| Open AccessMammalian display screening of diverse cystine-dense peptides for difficult to drug targets
Pathologies related to protein:protein interaction are hard to treat but cystine-dense peptides have the potential to disrupt such interactions. Here the authors develop a high-diversity mammalian cell screen for cystine-dense peptides with drug potential and use it to identify a YAP:TEAD inhibitor.
- Zachary R. Crook
- , Gregory P. Sevilla
- & James M. Olson
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| Open AccessA general pharmacodynamic interaction model identifies perpetrators and victims in drug interactions
Assessment of pharmacodynamic interactions is at the heart of combination therapy development. Here the authors introduce a general drug interaction scoring model that enables quantification of synergistic and antagonistic interactions and determination of the directionality of the interactions.
- Sebastian G. Wicha
- , Chunli Chen
- & Ulrika S. H. Simonsson
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Article
| Open AccessMolecular basis of differential 3′ splice site sensitivity to anti-tumor drugs targeting U2 snRNP
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
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Article
| Open AccessTargeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia
Ten-eleven translocation 1 (TET1) is a critical oncoprotein in AML. Here, the authors identify 2 compounds that target the binding of STAT3/5 specifically to the TET1 promoter, inhibiting its expression and AML cell viability.
- Xi Jiang
- , Chao Hu
- & Jianjun Chen
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Article
| Open AccessDendrogenin A drives LXR to trigger lethal autophagy in cancers
Dendrogenin A, cholesterol metabolite, has tumor suppressive properties but the mechanisms are unknown. Here the authors show that Dendrogenin A can induce autophagy-mediated cell death in both melanoma and acute myeloid leukaemia.
- Gregory Segala
- , Marion David
- & Sandrine Silvente-Poirot
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Article
| Open AccessChemogenomic analysis reveals key role for lysine acetylation in regulating Arc stability
The activity-regulated cytoskeleton-associated protein (Arc) has been implicated in synaptic plasticity and memory consolidation. Here the authors show that Arc acetylation regulates its stability and identify small molecules that modulate Arc expression.
- Jasmin Lalonde
- , Surya A. Reis
- & Stephen J. Haggarty
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| Open AccessOrganocatalytic enantio- and diastereoselective cycloetherification via dynamic kinetic resolution of chiral cyanohydrins
Enantioselective synthesis of six-membered oxacycles with multiple stereogenic centres is essential for the discovery of new therapeutic agents. Here the authors show organocatalytic cycloetherification for the highly enantio- and diastereoselective synthesis of tetrahydropyrans.
- Naoki Yoneda
- , Yuki Fujii
- & Seijiro Matsubara
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| Open AccessA water-soluble nucleolin aptamer-paclitaxel conjugate for tumor-specific targeting in ovarian cancer
Paclitaxel, a first line chemotherapeutic drug, suffers from poor water solubility and low tissue selectivity. Here, the authors report a water-soluble nucleolin aptamer-paclitaxel conjugate that selectively accumulates in ovarian tumor issues displaying reduced toxicity and improved activity profiles.
- Fangfei Li
- , Jun Lu
- & Ge Zhang
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Article
| Open AccessStructure of human lysosomal acid α-glucosidase–a guide for the treatment of Pompe disease
Pompe disease is caused by mutations in lysosomal acid α-glucosidase (GAA) and patients are being treated with recombinant human α-glucosidase (rhGAA). Here the authors present the crystal structures of rhGAA and its complexes with inhibitors and a pharmacological chaperone, which is important for drug development.
- Véronique Roig-Zamboni
- , Beatrice Cobucci-Ponzano
- & Gerlind Sulzenbacher
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| Open AccessA novel Fer/FerT targeting compound selectively evokes metabolic stress and necrotic death in malignant cells
The tyrosine-kinases Fer/FerT associate with the mitochondrial electron transport chain in cancer cells supporting their metabolic reprogramming. Here the authors discover a compound that disrupts Fer /FerT activity and selectively induces cell death of cancer cell lines displaying anti-tumor activity in vivo.
- Yoav Elkis
- , Moshe Cohen
- & Uri Nir
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| Open AccessControl of leucine-dependent mTORC1 pathway through chemical intervention of leucyl-tRNA synthetase and RagD interaction
Leucyl-tRNA synthetase (LRS) is a leucine sensor of the mTORC1 pathway. Here, the authors identify inhibitors of the GTPase activating function of LRS, not affecting its catalytic activity, and demonstrate that the leucine sensor function of LRS can be a new target for mTORC1 inhibition.
- Jong Hyun Kim
- , Chulho Lee
- & Sunghoon Kim
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Article
| Open AccessStapled peptide inhibitors of RAB25 target context-specific phenotypes in cancer
The Ras-family small GTPase RAB25 can exert both pro- and anti-oncogenic functions. Here, the authors develop all-hydrocarbon stabilized peptides targeting RAB25 and influencing the context-specificity phenotypes in cancer cell lines.
- Shreya Mitra
- , Jeffrey E. Montgomery
- & Raymond E. Moellering
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Article
| Open AccessA potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission
Protein kinases are promising drug targets for treatment of malaria. Here, starting with a medicinal chemistry approach, Baker et al. generate an imidazopyridine that selectively targets Plasmodium falciparum PKG, inhibits blood stage parasite growth in vitro and in mice and blocks transmission to mosquitoes.
- David A. Baker
- , Lindsay B. Stewart
- & Simon A. Osborne
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Article
| Open AccessStructure of the Rpn13-Rpn2 complex provides insights for Rpn13 and Uch37 as anticancer targets
In the proteasome, Rpn2 provides the docking site for substrate receptor Rpn13. Here the authors present the structure of human Rpn13 Pru domain bound to its binding site in Rpn2 and provide insights into the mode of action for Rpn13-targeting molecule RA190, which has anticancer properties.
- Xiuxiu Lu
- , Urszula Nowicka
- & Kylie J. Walters
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| Open AccessDiscovery of first-in-class reversible dual small molecule inhibitors against G9a and DNMTs in hematological malignancies
Epigenetic drugs are emerging as a powerful therapeutic option for cancer treatment. Here, the authors synthesized selective chemical probes that simultaneously inhibit the G9a and DNMTs methyltransferase activity and demonstrate their anti-tumour activity usingin vitro and in vivomodels of haematological neoplasia.
- Edurne San José-Enériz
- , Xabier Agirre
- & Felipe Prosper
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| Open AccessPotent antitumour activity of interleukin-2-Fc fusion proteins requires Fc-mediated depletion of regulatory T-cells
Interleukin-2 (IL-2) is a T-cell proliferating factor used for cancer immunotherapy. Here, the authors develop a long-lived variant of IL-2 that, mutated in its binding domain, drives a much more potent tumour regression by depleting CD25+ CD4+regulatory T-cells via targeting them for phagocytosis.
- Rodrigo Vazquez-Lombardi
- , Claudia Loetsch
- & Daniel Christ
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| Open AccessStat3 regulates centrosome clustering in cancer cells via Stathmin/PLK1
Cancer cells have amplified centrosomes and deal with this abnormality by clustering them together so that they can be segregated in daughter cells. Here the authors perform a screening looking for inhibitors of this clustering process and find that STAT3 regulates this process independently of its transcriptional function.
- Edward J. Morris
- , Eiko Kawamura
- & Shoukat Dedhar
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| Open AccessDeconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention
Buparlisib/BKM120 is in phase 3 clinical trials as a phosphoinositide 3-kinase (PI3K) inhibitor. Here, Bohnackeret al. combine chemical biology and structural biology approaches to segregate BKM120’s biological actions, and suggest that it causes mitotic arrest predominantly by binding microtubules and disrupting their dynamics.
- Thomas Bohnacker
- , Andrea E. Prota
- & Matthias P. Wymann
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| Open AccessArylmethylamino steroids as antiparasitic agents
Steroid units can facilitate membrane permeation and bioavailability in drugs. Here, using a medicinal chemistry program, Krieget al. identify an arylmethylamino steroid that kills Plasmodium parasites, likely through a chelate-based quinone methide mechanism, and has activity against Schistosoma mansoni.
- Reimar Krieg
- , Esther Jortzik
- & Katja Becker
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| Open AccessMutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome
Spliceosome mutations occur in approximately 50% of patients with myelodysplastic syndromes. Here, the authors show that tumour cells harbouring theS34F mutation in the U2AFspliceosome gene is sensitive to compounds that further perturb the spliceosome.
- Cara Lunn Shirai
- , Brian S. White
- & Matthew J. Walter
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Article
| Open AccessMechanistic evaluation and transcriptional signature of a glutathione S-transferase omega 1 inhibitor
Glutathione S-transferase omega 1 (GSTO1) is an atypical GST isoform overexpressed in several cancers that has been implicated in drug resistance. Here the authors identify a small molecule inhibitor of GSTO1 that effectively inhibits tumor growth in colon cancer models, and establish its mechanism of action.
- Kavya Ramkumar
- , Soma Samanta
- & Nouri Neamati
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| Open AccessDichotomy of cellular inhibition by small-molecule inhibitors revealed by single-cell analysis
Many drugs are small molecule inhibitors of cell signalling. Through single cell analysis and mathematical modelling here the authors show that cell-to-cell variability diversifies inhibition response into digital and analogue, and that the two translate into distinct long-term functional responses.
- Robert M. Vogel
- , Amir Erez
- & Grégoire Altan-Bonnet
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| Open AccessInfluenza B virus non-structural protein 1 counteracts ISG15 antiviral activity by sequestering ISGylated viral proteins
The ubiquitin-like protein ISG15 can be covalently linked to cellular and viral proteins, but the consequences of this ‘ISGylation’ remain largely unknown. Here, Zhao et al.show that ISGylation of the influenza B virus nucleoprotein inhibits formation of a functional viral replication complex.
- Chen Zhao
- , Haripriya Sridharan
- & Robert M. Krug
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| Open AccessOptoDyCE as an automated system for high-throughput all-optical dynamic cardiac electrophysiology
The efficiency of preclinical drug testing and characterization of cellular function can be improved through the use of optogenetic tools. Here Klimas et al. present and validate OptoDyCE, a fully automated system for all-optical high-throughput cardiac electrophysiology.
- Aleksandra Klimas
- , Christina M. Ambrosi
- & Emilia Entcheva
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| Open AccessInhibition of DYRK1A and GSK3B induces human β-cell proliferation
All forms of diabetes eventually lead to a reduction in insulin-secreting pancreatic β-cells. Here, the authors report aminopyrazine derivatives, which induce proliferation of rodent as well as human β-cells and improve glucose metabolism in a mouse model of type 1 diabetes.
- Weijun Shen
- , Brandon Taylor
- & Bryan Laffitte
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Alendronate inhalation ameliorates elastase-induced pulmonary emphysema in mice by induction of apoptosis of alveolar macrophages
Macrophages have a role in the pathogenesis of pulmonary emphysema. Here the authors show that inhalation—but not oral delivery—of the anti-osteoporosis drug alendronate attenuates lung damage in a mouse model of emphysema by inducing apoptosis of alveolar macrophages.
- Manabu Ueno
- , Toshitaka Maeno
- & Masahiko Kurabayashi
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| Open AccessStructural characterization of a protective epitope spanning A(H1N1)pdm09 influenza virus neuraminidase monomers
Neuraminidase inhibitors offer a line of defence against flu infections, but resistance can occur even in the absence of prior exposure. Here Wan et al. describe the mode of action of CD6, a monoclonal antibody that protects against a common influenza strain, as a new therapeutic intervention model.
- Hongquan Wan
- , Hua Yang
- & Maryna C. Eichelberger
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Structural mechanism of ergosterol regulation by fungal sterol transcription factor Upc2
In yeast, the transcription factor Upc2 regulates genes involved in ergosterol biosynthesis, but how its activity is regulated is unknown. Here Yang et al. present the structure of the Upc2 C-terminal domain and discover that it functions as a sensor of the ergosterol level, regulating the transcriptional activity and cellular localization of Upc2.
- Huiseon Yang
- , Junsen Tong
- & Young Jun Im
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Dietary restriction protects against experimental cerebral malaria via leptin modulation and T-cell mTORC1 suppression
Nutrition can affect the outcome of infectious diseases through its effects on pathogens and/or host immunity. Here, Mejia et al.show that dietary restriction protects from experimental cerebral malaria in mice through its effects on leptin and mTORC1 in T cells.
- Pedro Mejia
- , J. Humberto Treviño-Villarreal
- & James R. Mitchell
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Berberine activates thermogenesis in white and brown adipose tissue
Berberine is contained in some plant-derived medicines and is known to have anti-diabetic effects. Here the authors show that berberine activates thermogenesis in white and brown adipose tissues, thereby increasing organismal energy expenditure and limiting weight gain in genetically obese mice.
- Zhiguo Zhang
- , Huizhi Zhang
- & Guang Ning
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An endocytosis pathway initiated through neuropilin-1 and regulated by nutrient availability
CendR peptides, based on a C-terminal motif found in neuropilins, have been used to promote drug delivery to tumours by endocytosis. Pang et al. show that CendR peptides are taken up by a mechanistically distinct form of endocytosis that resembles macropinocytosis, and is stimulated by nutrient depletion.
- Hong-Bo Pang
- , Gary B. Braun
- & Erkki Ruoslahti
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Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease
Selective targeting of cancer cells may improve therapeutic efficacy while reducing adverse effects. Here, Ueki et al.report selective activation of an anticancer drug upon removal of an acetylated lysine group by histone deacetylases and the tumour-associated protease cathepsin L.
- Nobuhide Ueki
- , Siyeon Lee
- & Michael J. Hayman
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A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth
Epigenetic regulators are promising targets for cancer drugs, as they can modulate a broad range of transcriptional networks simultaneously. Here, the authors identify an inhibitor of Jumonji-family histone demethylases and show that it selectively kills cancer cells in mouse tumour models.
- Lei Wang
- , Jianjun Chang
- & Elisabeth D. Martinez
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Engineering the type III secretion system in non-replicating bacterial minicells for antigen delivery
Bacterial type III secretion systems (T3SS) improve the delivery of vaccine antigens and antigen-specific immune responses but require the use of live vaccines. Carleton et al. report the assembly of a functional T3SS in replication-incompetent bacterial minicells that can deliver vaccine antigens in vitro and in vivo.
- Heather A. Carleton
- , María Lara-Tejero
- & Jorge E. Galán
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Article
| Open AccessAn intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid
β-Catenin can be oncogenic but finding inhibitors has been a challenge. Here, five compounds are identified, which attenuate transcriptional β-catenin outputs in colorectal cancer cells, and the response to one of them is shown to require an intrinsically labile α-helix next to the BCL9-binding site in β-catenin.
- Marc de la Roche
- , Trevor J. Rutherford
- & Mariann Bienz