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| Open AccessGenetic drug target validation using Mendelian randomisation
Mendelian randomisation (MR) analysis of drug targets has potential to aid drug development. Here, the authors introduce a mathematical framework to elucidate this specific application of MR.
- Amand F. Schmidt
- , Chris Finan
- & Aroon D. Hingorani
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Article
| Open AccessStructural plasticity of SARS-CoV-2 3CL Mpro active site cavity revealed by room temperature X-ray crystallography
The SARS-CoV-2 3CL main protease (3CL Mpro) is a chymotrypsin-like protease that facilitates the production of non-structural proteins, which are essential for viral replication and is therefore of great interest as a drug target. Here, the authors present the 2.30 Å room temperature crystal structure of ligand-free 3CL Mpro and compare it with the earlier determined low-temperature ligand-free and inhibitor-bound crystal structures.
- Daniel W. Kneller
- , Gwyndalyn Phillips
- & Andrey Kovalevsky
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Article
| Open AccessPharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response
Protein arginine methyltransferases (PRMTs) are increasingly recognized as potential therapeutic targets but PRMT7 remains an understudied member of this enzyme family. Here, the authors develop a chemical probe for PRMT7 and apply it to elucidate the role of PRMT7 in the cellular stress response.
- Magdalena M. Szewczyk
- , Yoshinori Ishikawa
- & Dalia Barsyte-Lovejoy
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Article
| Open AccessElucidating target specificity of the taccalonolide covalent microtubule stabilizers employing a combinatorial chemical approach
Taccalonolide microtubule stabilizers covalently bind β-tubulin and overcome taxane resistance mechanisms. Here, the authors synthesized fluorogenic taccalonolide probes and investigated the specificity of taccalonolide binding to β-tubulin and the molecular interactions between drug and target,
- Lin Du
- , Samantha S. Yee
- & April L. Risinger
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Article
| Open AccessTargeting mutant p53-expressing tumours with a T cell receptor-like antibody specific for a wild-type antigen
Several cancers harbour mutant p53 and express higher levels of p53-derived peptide-MHCs. Here, the authors report affinity matured human antibody, P1C1TM, specific for the p53125-134 peptide in complex with the HLA-A24 class I MHC molecule and show its efficacy and specificity for mutant p53 expressing tumours.
- Lionel Low
- , Angeline Goh
- & Cheng-I Wang
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Article
| Open AccessPlasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development
New tuberculosis therapies, targeting respiratory chain components of Mycobacterium tuberculosis, are under development. Here the authors show that, contrary to common belief, some of these components are not essential for pathogen viability and/or virulence in animal models of infection.
- Tiago Beites
- , Kathryn O’Brien
- & Dirk Schnappinger
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Article
| Open AccessFelodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing
A key challenge is to find/re-purpose approved drugs that could be used in humans to induce autophagy-associated clearance of neurodegenerative proteins. Here, authors demonstrate that felodipine, an anti-hypertensive drug, can induce autophagy and clear a variety of aggregated neurodegenerative disease-associated proteins in mouse brains at plasma concentrations similar to those that would be seen in humans taking the drug.
- Farah H. Siddiqi
- , Fiona M. Menzies
- & David C. Rubinsztein
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Article
| Open AccessThe compound TB47 is highly bactericidal against Mycobacterium ulcerans in a Buruli ulcer mouse model
Combination therapy for Buruli ulcer (BU) is suboptimal. Here, Liu et al. show that the candidate drug TB47 has potent bactericidal activity against Mycobacterium ulcerans in vitro and in a mouse model, which underscores its potential for shortening the course of BU and treating other mycobacterial diseases.
- Yang Liu
- , Yamin Gao
- & Tianyu Zhang
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Article
| Open AccessStructural basis for species-selective targeting of Hsp90 in a pathogenic fungus
The chaperone Hsp90 is a potential target for the development of drugs against fungal pathogens. Here the authors determine the structure of the Hsp90 nucleotide-binding domain from Candida albicans, which they use to design an inhibitor and demonstrate its selectivity for the fungal enzyme, both biochemically and in cells.
- Luke Whitesell
- , Nicole Robbins
- & Leah E. Cowen
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Article
| Open AccessThe transcription factor STAT5 catalyzes Mannich ligation reactions yielding inhibitors of leukemic cell proliferation
The oncogene STAT5 is involved in cancer cell proliferation. Here, the authors use STAT5 protein to assemble its own small molecule inhibitors via Mannich ligation (three-component-reactions) and show that the resultant ligands can inhibit the proliferation of cancer cells in a mouse model.
- Ee Lin Wong
- , Eric Nawrotzky
- & Jörg Rademann
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Article
| Open AccessOridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity
The small molecule oridonin (Ori) from the traditional Chinese herb Rabdosia rubescens has anti-inflammatory activity. Here the authors show that Ori can be covalently linked to NLRP3 to prevent assembly of the NLRP3 inflammasome, and to ameliorate inflammation in several mouse disease models.
- Hongbin He
- , Hua Jiang
- & Rongbin Zhou
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Article
| Open AccessTargeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes
Spinal muscular atrophy (SMA) is an autosomal recessive disorder with no present cure. Here the authors perform an in vitro screening leading to the identification of a small molecule that alters the conformational dynamics of the TSL2 RNA structure and acts as a modulator of SMN exon 7 splicing.
- Amparo Garcia-Lopez
- , Francesca Tessaro
- & Leonardo Scapozza
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Article
| Open AccessCalreticulin and integrin alpha dissociation induces anti-inflammatory programming in animal models of inflammatory bowel disease
Inflammatory bowel disease (IBD) is initiated by integrins-mediated leukocyte adhesion to the activated colonic microvascular endothelium. Here, the authors show that inhibition of the calreticulin binding to integrin α subunits ameliorates the severity of IBD in animal models.
- Masayoshi Ohkuro
- , Jun-Dal Kim
- & Akiyoshi Fukamizu
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Article
| Open AccessPlasmepsin II–III copy number accounts for bimodal piperaquine resistance among Cambodian Plasmodium falciparum
Piperaquine (PPQ) resistance of Plasmodium is an increasing problem. Here, Bopp et al. find a bimodal dose−response curve of Cambodian isolates exposed to PPQ, with the area under the curve correlating with in vitro PPQ resistance, and show the importance of Plasmepsin II–III copy number to PPQ resistance.
- Selina Bopp
- , Pamela Magistrado
- & Sarah K. Volkman
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Article
| Open AccessIntegrated genomics and functional validation identifies malignant cell specific dependencies in triple negative breast cancer
Triple negative breast cancers harbor multiple copy number aberrations driving gene expression changes thought to underpin their malignant phenotypes. Here the authors integrate these features, finding and functionally validating 37 gene addictions among which they identify the mechanism of addiction to KIFC1, a potential selective drug target.
- Nirmesh Patel
- , Daniel Weekes
- & Andrew N. J. Tutt
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Correspondence
| Open AccessCorrespondence: Compound 17b and formyl peptide receptor biased agonism in relation to cardioprotective effects in ischaemia-reperfusion injury
- Agostino Cilibrizzi
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Article
| Open AccessA small molecule inhibitor of Rheb selectively targets mTORC1 signaling
Aberrant mTORC1 signaling is linked to several chronic diseases. Here, the authors develop a small molecule inhibitor that binds the small G-protein Rheb and selectively blocks mTORC1 signaling, holding potential for therapeutic applications.
- Sarah J. Mahoney
- , Sridhar Narayan
- & Eddine Saiah
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Article
| Open AccessTarget identification of small molecules using large-scale CRISPR-Cas mutagenesis scanning of essential genes
Cancer therapy drugs are designed to target genetic vulnerabilities, but loss-of-function screens often fail to identify essential genes in drug mechanism studies. Here the authors demonstrate CRISPRres, which exploits in-frame variation generated by indel formation to discover gene-drug interactions.
- Jasper Edgar Neggers
- , Bert Kwanten
- & Dirk Daelemans
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Article
| Open AccessOvercoming mcr-1 mediated colistin resistance with colistin in combination with other antibiotics
The plasmid-borne mcr-1 gene confers resistance to the antibiotic colistin. Here, MacNair et al. show that mcr-1 positive bacteria are however susceptible to colistin-mediated disruption of the outer membrane, and can be killed in vitro and in vivo by combining colistin with other antibiotics.
- Craig R. MacNair
- , Jonathan M. Stokes
- & Eric D. Brown
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Article
| Open AccessTargeted NUDT5 inhibitors block hormone signaling in breast cancer cells
NUDIX hydrolases are an important family of nucleotide-metabolizing enzymes. Here, the authors identify potent, small molecule inhibitors of NUDT5, which is implicated in ADP-ribose and 8-oxo-guanine metabolism, and confirm its role in gene regulation and proliferation in breast cancer cells.
- Brent D. G. Page
- , Nicholas C. K. Valerie
- & Thomas Helleday
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Article
| Open AccessNF-κB inducing kinase is a therapeutic target for systemic lupus erythematosus
Clinical trials of BAFF blockade with belimumab have shown partial efficacy for the treatment of systemic lupus erythematosus (SLE), so other therapeutic options are required. Here, the authors present a new small molecule inhibitor that targets NIK with a similar efficacy to BAFF inhibition in two mouse models of SLE.
- Hans D. Brightbill
- , Eric Suto
- & Nico Ghilardi
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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 AccessA potent small-molecule inhibitor of the DCN1-UBC12 interaction that selectively blocks cullin 3 neddylation
Cullins are central components of the ubiquitin-proteosome system and are activated via a neddylation process mediated by the DCN1–UBC12 complex. Here, the authors develop a small molecule inhibitor of the DCN1–UBC12 interaction that specifically blocks cullin 3 neddylation and can be used to probe the cellular function of cullin 3.
- Haibin Zhou
- , Jianfeng Lu
- & Shaomeng Wang
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Article
| Open AccessAntisense oligonucleotide-mediated Dnm2 knockdown prevents and reverts myotubular myopathy in mice
X-linked myotubular myopathy is caused by mutations in the gene coding for myotubularin 1, and is characterized by overexpression of dynamin 2. Here the authors develop antisense oligonucleotides to dynamin 2, and show that systemic injection leads to improved pathology in mice.
- Hichem Tasfaout
- , Suzie Buono
- & Jocelyn Laporte
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Article
| Open AccessSelective BET bromodomain inhibition as an antifungal therapeutic strategy
BET proteins bind chromatin through their bromodomains (BDs) to regulate transcription and chromatin remodelling. Here, the authors show that the BET protein Bdf1 is essential for the fungal pathogenCandida albicans, and report compounds that inhibit the Bdf1 BDs with high selectivity over human BDs.
- Flore Mietton
- , Elena Ferri
- & Carlo Petosa
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Article
| Open AccessPharmacological inhibition of adipose triglyceride lipase corrects high-fat diet-induced insulin resistance and hepatosteatosis in mice
The enzyme Atgl participates in the breakdown of lipids in adipose tissue. Here the authors show that pharmacological inhibition of Atgl reduces weight gain and improves metabolic health in mice fed a high-fat diet, without causing adverse effects in cardiac muscle associated with genetic depletion ofAtgl.
- Martina Schweiger
- , Matthias Romauch
- & Rudolf Zechner
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Article
| Open AccessCannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity
CB2 receptor agonists are developed as potential analgesics or immune-modulatory compounds. Here, the authors characterize the pharmacological properties of widely used CB2 receptor agonists and antagonists, recommending three that appear most suitable for in vitro and in vivostudies.
- Marjolein Soethoudt
- , Uwe Grether
- & Mario van der Stelt
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Article
| Open AccessAilanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer
Prostate cancers often become castration resistant due to alternative expression of androgen receptor (AR) splice variants. Here, the authors screened a library of natural compounds and identified Ailanthone as a potent inhibitor of AR through its binding to the co-chaperone protein p23 that, by preventing AR interaction with HSP90, results in ubiquitin/proteasome-mediated degradation of the receptor.
- Yundong He
- , Shihong Peng
- & Mingyao Liu
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Article
| Open AccessPotent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition
Small molecule probes used to trigger hypoxic response by activating hypoxia inducible factors (HIFs) often lack specificity. Here the authors report a potent small molecule inhibitor that induces hypoxic response by blocking VHL:HIF interactions, providing a selective route to probe hypoxic signalling.
- Julianty Frost
- , Carles Galdeano
- & Alessio Ciulli
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Article
| Open AccessTargeted inhibition of the COP9 signalosome for treatment of cancer
Dysregulation of protein degradation by the ubiquitin-proteasome system is a feature commonly associated with cancer. Here, the authors develop an orally available small molecule that inhibits CSN5, the proteolytic subunit of the COP9 signalosome, and blocks tumour growth in a xenograft model.
- Anita Schlierf
- , Eva Altmann
- & Bruno Martoglio
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Article
| Open AccessStructures and stabilization of kinetoplastid-specific split rRNAs revealed by comparing leishmanial and human ribosomes
Leishmania donovani is a protozoan parasite that can cause fatal infections in humans. Here the authors present a high resolution cryoEM structure of the L. donovani80S ribosome and compare it to its human counterpart to provide insight into the basis for drug selectivity towards this eukaryotic parasite.
- Xing Zhang
- , Mason Lai
- & Z. Hong Zhou
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Article
| Open AccessCETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil
Drugs therapeutic efficacy relies on their capability of binding the relevant targets in a physiological environment, which has so far been hard to measure. Here, the authors present a compound library screen based on a target engagement assay that reports on protein stability upon ligands binding in cell.
- Helena Almqvist
- , Hanna Axelsson
- & Pär Nordlund
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Article
| Open AccessChemical and genetic validation of thiamine utilization as an antimalarial drug target
The malaria parasite Plasmodium falciparum utilizes thiamine for the production of essential enzymatic cofactors. Chan et al. show that inhibition of thiamine utilization with oxythiamine inhibits proliferation of P. falciparumand reduces parasite growth in a mouse model of malaria infection.
- Xie Wah Audrey Chan
- , Carsten Wrenger
- & Kevin J. Saliba