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| Open AccessTargeting HDAC6 to treat heart failure with preserved ejection fraction in mice
HFpEF has few effective treatments. Here, the authors show that inhibition of histone deacetylase 6 (HDAC6) with TYA-018 reverses established HFpEF symptoms in mice, comparably to the use of a sodium-glucose cotransporter 2 inhibitor; highlighting HDAC6 as a potential target to treat HFpEF.
- Sara Ranjbarvaziri
- , Aliya Zeng
- & Jin Yang
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Article
| Open AccessLeukemic stem cells activate lineage inappropriate signalling pathways to promote their growth
In Acute Myeloid Leukemia a population of quiescent leukemic stem cells (LSCs) evade chemotherapy and initiate relapse, but what makes them grow again is unknown. Here, the authors show (i) that LSCs hijack ectopic signaling pathways to kick-start their growth and (ii) that growth can be blocked with repurposed drugs in t(8;21) AML sub-type.
- Sophie G. Kellaway
- , Sandeep Potluri
- & Constanze Bonifer
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Article
| Open AccessStructure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity
Wang et al. report on an inhibitor of the lysine methyltransferase KMT9 with cellular activity. The inhibitor blocks proliferation of androgen-resistant prostate cancer cells, opening therapeutics avenues to treat this type of cancer.
- Sheng Wang
- , Sebastian O. Klein
- & Roland Schüle
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Article
| Open AccessA genome-scale metabolic model of parasitic whipworm
In this work, Bay et al describe the construction of the first genome-scale metabolic model for the parasitic whipworm, Trichuris muris and use it to identify novel metabolic pathways and predict critical enzymes and essential metabolites for worm survival.
- Ömer F. Bay
- , Kelly S. Hayes
- & Ian S. Roberts
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Article
| Open AccessActivation of the integrated stress response by inhibitors of its kinases
The integrated stress response (ISR) is the focus of numerous investigations and drug development programs. Here, the authors show that ATP-competitive inhibitors of ISR kinases PERK, PKR and GCN2 inhibit their targets but activate the ISR by directly binding to and activating a sister ISR kinase.
- Maria Szaruga
- , Dino A. Janssen
- & Anne Bertolotti
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Review Article
| Open AccessChallenges in developing Geroscience trials
Geroscience is becoming a major hope for preventing age-related diseases and loss of function by targeting biological mechanisms of aging. This article reports a discussion of a research Task Force on the challenges posed by the clinical research in Geroscience so that future gerotherapeutic clinical trials can be conducted successfully.
- Yves Rolland
- , Felipe Sierra
- & Alex Zhavoronkov
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Article
| Open AccessLenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation
Lenalidomide is effective for treating several hematological cancers but has teratogenic effect on the fetus. Here, the authors identify modifications that make lenalidomide more selective and effective when used as a stand-alone molecular glue or integrated in PROTACs.
- Satoshi Yamanaka
- , Hirotake Furihata
- & Tatsuya Sawasaki
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Article
| Open AccessTargeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction
Dynamin-related protein 1 (Drp1) mediates physiological and pathological mitochondrial fission, and the latter can be selectively blocked by a peptide inhibitor. Here, the authors identify a small molecule that mimics the benefits of this peptide inhibitor in cells and a mouse model of endotoxemia.
- Luis Rios
- , Suman Pokhrel
- & Daria Mochly-Rosen
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Article
| Open AccessLateral membrane organization as target of an antimicrobial peptidomimetic compound
The mechanism of action of the antibacterial tripeptide AMC-109 is unclear. Here, Melcrová et al. show that AMC-109 self-assembles into stable aggregates with a cationic surface, and then individual peptides insert into the bacterial membrane and disrupt membrane nanodomains, thus affecting membrane function without forming pores.
- Adéla Melcrová
- , Sourav Maity
- & Wouter H. Roos
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Article
| Open AccessInduction of lysosomal exocytosis and biogenesis via TRPML1 activation for the treatment of uranium-induced nephrotoxicity
The roles of lysosomes in uranium (U) decorporation and detoxification remain to be elucidated. Here, the authors demonstrate that TRPML1 activation is an attractive therapeutic strategy to induce lysosomal exocytosis and biogenesis for the treatment of U-induced nephrotoxicity.
- Dengqin Zhong
- , Ruiyun Wang
- & Honghong Chen
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Article
| Open AccessDurable contraception in the female domestic cat using viral-vectored delivery of a feline anti-Müllerian hormone transgene
This study demonstrates the safety and long-term efficacy of a single-dose, injectable contraceptive in female domestic cats. Treated females remained contracepted for over two years, and did not ovulate or produce kittens when paired with males.
- Lindsey M. Vansandt
- , Marie-Charlotte Meinsohn
- & David Pépin
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Article
| Open AccessTherapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD4-selective WNT surrogate in mice
The WNT/b-catenin pathway is essential for bloodbrain barrier (BBB) and blood-retina barrier (BRB) function. A bioengineered FZD4-selective WNT surrogate demonstrated systemic efficacy during BRB and ischemic stroke BBB dysfunction in mice.
- Jie Ding
- , Sung-Jin Lee
- & Calvin J. Kuo
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Article
| Open AccessMechanism of action for small-molecule inhibitors of triacylglycerol synthesis
Sui et al. elucidate the mechanisms of action for small molecule inhibitors of human triacylglycerol synthesis enzyme DGAT1 and provide insights into how these inhibitors achieve selectivity for DGAT1 rather than other closely related MBOAT enzymes.
- Xuewu Sui
- , Kun Wang
- & Tobias C. Walther
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Article
| Open AccessNanoparticle-mediated TRPV1 channel blockade amplifies cancer thermo-immunotherapy via heat shock factor 1 modulation
TRPV1 has been associated with proliferation and survival of tumors, and can be activated by heat and other stimuli. Here, the authors block TRPV1 using photothermal nanoparticles encapsulating a TRPV1 antagonist in different cancer types, which can enhance thermo-immunotherapy in pancreatic cancer models.
- Ting Li
- , Shuhui Jiang
- & Huabing Chen
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Article
| Open AccessOn-demand male contraception via acute inhibition of soluble adenylyl cyclase
Half of all pregnancies are unintended; thus, existing family planning options are inadequate. This proof-of-concept study validates an on-demand contraception strategy for men, showing high effectiveness in quickly and temporarily reducing male fertility in mice.
- Melanie Balbach
- , Thomas Rossetti
- & Lonny R. Levin
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Article
| Open AccessSmall molecule inhibitors of 15-PGDH exploit a physiologic induced-fit closing system
Inhibition of 15-prostaglandin dehydrogenase (15-PGDH) is a promising therapeutic target for regenerative medicine. We report the structure of 15-PGDH in complex with two different inhibitors. Unexpectedly, access to the binding pocket is regulated by a dynamic “lid” of the enzyme.
- Wei Huang
- , Hongyun Li
- & Derek J. Taylor
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Comment
| Open AccessA two-faced selectivity solution to target SMARCA2 for cancer therapy
Two new studies exploring PROTAC-mediated degradation of SMARCA2 for cancer therapy solve an apparently intractable selectivity challenge with SMARCA4 by utilising the requirement for a productive ternary complex between the protein, PROTAC and ligase complex.
- John D. Harling
- & Christopher P. Tinworth
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Article
| Open AccessPharmacological inhibition of Lin28 promotes ketogenesis and restores lipid homeostasis in models of non-alcoholic fatty liver disease
The Lin28/let-7 axis regulates metabolic pathways in normal and pathological contexts. Here the authors show that pharmacological inhibition of Lin28 protects against lipid accumulation in multiple preclinical models of nonalcoholic fatty liver disease.
- Evangelia Lekka
- , Aleksandra Kokanovic
- & Jonathan Hall
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Article
| Open AccessStructural basis of synthetic agonist activation of the nuclear receptor REV-ERB
The nuclear receptor REV-ERBα is a receptor for heme and plays a role in a range of physiological processes. Here, the authors provide the first structure of REV-ERB bound to a synthetic nonporphyrin ligand defining key mechanistic differences to how heme binds.
- Meghan H. Murray
- , Aurore Cecile Valfort
- & Thomas P. Burris
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Article
| Open AccessStructural dynamics of AAA + ATPase Drg1 and mechanism of benzo-diazaborine inhibition
Drg1 is a cytoplasmic AAA + ATPase responsible for releasing Rlp24 during ribosome assembly. Here, the authors show that Drg1 structurally and functionally shares many regulatory features with that of Cdc48/p97, suggesting a unfoldase role for Drg1.
- Chengying Ma
- , Damu Wu
- & Ning Gao
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Article
| Open AccessStructural 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
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Article
| Open AccessSystematic profiling of conditional degron tag technologies for target validation studies
Conditional Degron Tags are a valuable tool to validate and study novel therapeutic targets. Here, the authors compared 5 orthogonal tags across 16 unique proteins and provide a panel of vectors for users to systematically screen the tags with their own protein of interest.
- Daniel P. Bondeson
- , Zachary Mullin-Bernstein
- & Alessandra Ianari
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Article
| Open AccessTackling recalcitrant Pseudomonas aeruginosa infections in critical illness via anti-virulence monotherapy
Pseudomonas aeruginosa infections are increasingly difficult to treat due to the development of antimicrobial resistance. Here, the authors describe the synthesis, characterisation and efficacy of a quorum sensing inhibitor.
- Vijay K. Singh
- , Marianna Almpani
- & Laurence G. Rahme
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Article
| Open AccessA TrkB agonist prodrug prevents bone loss via inhibiting asparagine endopeptidase and increasing osteoprotegerin
BDNS and TrkB are involved in bone fracture healing by inhibiting AEP. Here the authors show that a TrkB agonist prodrug can inhibit AEP and promote bone formation in osteoporotic mice.
- Jing Xiong
- , Jianming Liao
- & Keqiang Ye
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Article
| Open AccessAccurate determination of CRISPR-mediated gene fitness in transplantable tumours
Gene fitness and essentiality analyses using in vivo cancer models are challenging due to multiple confounders. Here, the authors develop a quantitative approach to study CRISPR-transduced patient-derived xenografts, which they use to analyse in vivo gene fitness in breast cancers and the biological features that influence uncertainty in fitness estimation.
- Peter Eirew
- , Ciara O’Flanagan
- & Samuel Aparicio
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Article
| Open AccessSelective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression
Wall et al. describe the selective activation of an adenosine A1 receptor-mediated intracellular pathway that provides potent analgesia in the absence of sedation or cardiorespiratory depression, paving the way for novel medicines based on the far-reaching concept of selective Gα agonism.
- Mark J. Wall
- , Emily Hill
- & Bruno G. Frenguelli
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Article
| Open AccessDevelopment of NanoLuc-targeting protein degraders and a universal reporter system to benchmark tag-targeted degradation platforms
t ag-T argetedP roteinD egrader (tTPD) systems are powerful tools for preclinical target validation. Here the authors extend the tTPD platform by developing NanoTACs that degrade NanoLuc tagged substrates and benchmark each tTPD system using an interchangeable tag reporter system.- Christoph Grohmann
- , Charlene M. Magtoto
- & Rebecca Feltham
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Article
| Open AccessDistinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors
How resistance to different classes of AKT inhibitors can emerge is unclear. Here, the authors show that resistance to allosteric inhibitors is mainly due to mutation of AKT1 while the ATP competitive resistance is driven by activation of PIM kinases in prostate cancer models.
- Kristin M. Zimmerman Savill
- , Brian B. Lee
- & Kui Lin
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Article
| Open AccessInhibition of lung microbiota-derived proapoptotic peptides ameliorates acute exacerbation of pulmonary fibrosis
Here, the authors show that treatment with a monoclonal neutralizing antibody against the lung microbiota-derived proapoptotic peptide corisin ameliorates acute exacerbation of pulmonary fibrosis and severity of endotoxin-induced acute lung injury in mice.
- Corina N. D’Alessandro-Gabazza
- , Taro Yasuma
- & Esteban C. Gabazza
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Article
| Open AccessCo-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer
Deregulation of the BCL-2 family interactions ensures cancer resistance to apoptosis and is a major challenge to current treatments. Here the authors describe a novel therapeutic strategy to overcome two anti-apoptotic mechanisms for cancer therapy.
- Andrea Lopez
- , Denis E. Reyna
- & Evripidis Gavathiotis
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Article
| Open AccessTrkB agonist antibody ameliorates fertility deficits in aged and cyclophosphamide-induced premature ovarian failure model mice
Qin et al. report that an agonistic antibody targeting the BDNF receptor TrkB promotes follicle development and oocyte maturation, and reverse ovarian deficits and infertility in aged and cyclophosphamide-induced premature ovarian failure model mice.
- Xunsi Qin
- , Yue Zhao
- & Bai Lu
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Article
| Open AccessPyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps
Efflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, the authors identify pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through allosteric inhibition of its primary RND transporter.
- Coline Plé
- , Heng-Keat Tam
- & Ruben C. Hartkoorn
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Article
| Open AccessA proximity biotinylation-based approach to identify protein-E3 ligase interactions induced by PROTACs and molecular glues
PROTACs and molecular glues target E3 ubiquitin ligases to substrate proteins. Here, the authors develop a proximity biotinylation-based method to identify drug-induced E3 ligase-substrate interactions, enabling the assessment of the target spectrum of PROTACs and molecular glues in cells.
- Satoshi Yamanaka
- , Yuto Horiuchi
- & Tatsuya Sawasaki
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Article
| Open AccessSmall molecule splicing modifiers with systemic HTT-lowering activity
Here the authors describe the discovery of a class of small molecule splicing modifiers which are orally bioavailable, cross the blood-brain barrier, and lower levels of huntingtin in a mouse model of Huntington’s disease (HD).
- Anuradha Bhattacharyya
- , Christopher R. Trotta
- & Stuart W. Peltz
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Article
| Open AccessValidation of lipid-related therapeutic targets for coronary heart disease prevention using human genetics
Drug target Mendelian randomization (MR) uses genetic variation in or near a gene encoding a drug target to anticipate the effect of drug action on the same target. Using drug target MR, the authors prioritized 30 targets that might elicit beneficial effects in the prevention or treatment of coronary heart disease.
- María Gordillo-Marañón
- , Magdalena Zwierzyna
- & Chris Finan
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Article
| Open AccessCholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease
Despite being studied in clinical trials, CETP inhibitors are not yet an approved treatment for coronary heart disease. Here, by analyzing results from clinical trials and drug target mendelian randomization studies, the authors demonstrate that previous failure of CETP inhibitors are likely compound and not drug target-related.
- Amand F. Schmidt
- , Nicholas B. Hunt
- & Chris Finan
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Article
| Open AccessGenetic and chemical inhibition of IRF5 suppresses pre-existing mouse lupus-like disease
IRF5 is a potential target for therapy in systemic lupus erythematosus (SLE). Here the authors show using mouse SLE-like models that genetic or chemical inhibition of IRF5 after SLE onset could be more effective than, or an add on for, currently utilised type I interferon inhibition.
- Tatsuma Ban
- , Masako Kikuchi
- & Tomohiko Tamura
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Article
| Open AccessSelective inhibition of cullin 3 neddylation through covalent targeting DCN1 protects mice from acetaminophen-induced liver toxicity
Activation of cullin-RING ligases can be inhibited by targeting DCN1, but selective DCN1 inhibitors with in vivo activity are lacking. Here, the authors develop covalent DCN1 inhibitors that selectively and potently inhibit cullin-3 activation and downstream functions in cells and in mice.
- Haibin Zhou
- , Jianfeng Lu
- & Shaomeng Wang
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Article
| Open AccessMolecular basis of V-ATPase inhibition by bafilomycin A1
Bafilomycin A1, a member of macrolide antibiotics and an autophagy inhibitor, serves as a specific and potent V-ATPases inhibitor. Here authors report the cryo-EM structure of bafilomycin A1-bound V-ATPase with six bafilomycin A1 molecules bound to the c-ring and reveal the molecular basis for Bafilomycin A1 inhibition of the V-ATPase.
- Rong Wang
- , Jin Wang
- & Xiaochun Li
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Article
| Open AccessIdentification of CD318, TSPAN8 and CD66c as target candidates for CAR T cell based immunotherapy of pancreatic adenocarcinoma
There is an unmet clinical need to identify therapeutic options for the treatment of pancreatic cancer (PDAC). Here the authors present a systematic screening approach for the identification of potential PDAC cell surface target candidates for CAR-T cell based immunotherapy, followed by their functional validation in preclinical models.
- Daniel Schäfer
- , Stefan Tomiuk
- & Olaf Hardt
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Article
| Open AccessEltrombopag directly inhibits BAX and prevents cell death
The BCL-2 family protein BAX functions to regulate mitochondria-driven cell death. Here the authors show that the drug Eltrombopag inhibits BAX and prevents apoptosis induced by cytotoxic stimuli.
- Adam Z. Spitz
- , Emmanouil Zacharioudakis
- & Evripidis Gavathiotis
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Article
| Open AccessHistone Parylation factor 1 contributes to the inhibition of PARP1 by cancer drugs
PARP1 is the target of clinically approved anti-cancer drugs whose in vivo efficacy has been hard to predict. Here the authors show how an altered active site formed between PARP1 and Histone PARylation Factor 1 (HPF1) changes the efficacy of some of these inhibitors.
- Johannes Rudolph
- , Genevieve Roberts
- & Karolin Luger
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Article
| Open AccessStructural basis of malaria parasite phenylalanine tRNA-synthetase inhibition by bicyclic azetidines
Bicyclic azetidine inhibitors are promising antimalarials that target the Plasmodium cytosolic phenylalanine tRNAsynthetase (cFRS). Here, Sharma et al. provide the biochemical and structural basis of its mechanism using co-crystal structure of PvcFRS with BRD1389.
- Manmohan Sharma
- , Nipun Malhotra
- & Amit Sharma
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Article
| Open AccessGenetic and pharmacological inhibition of the nuclear receptor RORα regulates TH17 driven inflammatory disorders
Unlike RORα, which has been thought to be somewhat redundant, RORγt has been well characterized in its function and contribution to the development of Th17 cells. Here the authors show that RORα is important in Th17 differentiation and that RORα deletion or a small molecule inhibitor of RORα can reduce disease in EAE and colitis mouse models.
- Ran Wang
- , Sean Campbell
- & Laura A. Solt
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Article
| Open AccessRapid and direct control of target protein levels with VHL-recruiting dTAG molecules
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
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Article
| Open AccessInhibitors of BRAF dimers using an allosteric site
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
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Article
| 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