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| 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 AccessCharacterisation of IL-23 receptor antagonists and disease relevant mutants using fluorescent probes
The single nucleotide polymorphism C115Y in the IL-23 receptor is associated with autoinflammatory diseases. Here the authors demonstrate that this mutation prevents the binding of a fluorescent cyclic peptide and IL-23 to the IL-23 receptor.
- Charles S. Lay
- , Albert Isidro-Llobet
- & Stephen J. Hill
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Article
| Open AccessHigh-affinity peptides developed against calprotectin and their application as synthetic ligands in diagnostic assays
A peptide was developed that binds to calprotectin, a marker of major inflammatory disorders, and found to be suited for diagnostic tests. The use of synthetic peptides in assays is of great interest due to their high precision, robustness and low price.
- Cristina Díaz-Perlas
- , Benjamin Ricken
- & Christian Heinis
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| Open AccessIdentification of indocyanine green as a STT3B inhibitor against mushroom α-amanitin cytotoxicity
There is currently no specific antidote for death cap mushroom poisoning treatment. Here, the authors identify STT3B as a druggable target and show that indocyanine green is a STT3B inhibitor that can block α-amanitin toxicity in cell lines, liver organoids and mice.
- Bei Wang
- , Arabella H. Wan
- & Qiao-Ping Wang
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Article
| Open AccessGalNAc-Lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy
Kasiewicz et al. describe a structure-guided rational design approach to optimize a new GalNAc-Lipid nanoparticle that enables delivery of a base editing therapy in both low-density lipoprotein receptor-deficient and wild-type nonclinical models.
- Lisa N. Kasiewicz
- , Souvik Biswas
- & Andrew M. Bellinger
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Article
| Open AccessRegorafenib inhibits EphA2 phosphorylation and leads to liver damage via the ERK/MDM2/p53 axis
The mechanism underlying regorafenib’s hepatotoxicity during anticancer therapy remains elusive. Here, the authors show regorafenib inhibits the phosphorylation of EphA2 at Ser897 resulting in the accumulation of p53 and contributes to hepatocytes apoptosis and the formation of hepatotoxicity.
- Hao Yan
- , Wentong Wu
- & Peihua Luo
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Article
| Open AccessA first-in-class inhibitor of Hsp110 molecular chaperones of pathogenic fungi
Hsp110 chaperones play important roles in protein homeostasis in eukaryotes. Here, the authors identify a small compound that inhibits fungal Hsp110s as well as the growth and viability of the pathogenic fungus Candida albicans, supporting Hsp110s as targets for development of new antifungal drugs.
- Liqing Hu
- , Cancan Sun
- & Qinglian Liu
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Article
| Open AccessTranslational reprogramming as a driver of antimony-drug resistance in Leishmania
Leishmania is a unicellular protozoan that has limited transcriptional control. Here, the authors show that translational control is a major mechanism of antimony drug resistance in Leishmania. They observe a dramatic translatome reprogramming during development of resistance to the drug and report translational control as a major driver of antimony-resistant phenotypes.
- Sneider Alexander Gutierrez Guarnizo
- , Elena B. Tikhonova
- & Zemfira N. Karamysheva
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Article
| Open AccessKK-LC-1 as a therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer
The presence of breast cancer stem cells is associated with therapy resistance in patients with triple-negative breast cancer (TNBC). Here, the authors identify KK-LC-1-mediated YAP signaling as a driver of TNBC stemness and develop a therapeutic molecule to target this axis in preclinical models of TNBC.
- Jiawen Bu
- , Yixiao Zhang
- & Caigang Liu
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Article
| Open AccessMachine learning-driven multifunctional peptide engineering for sustained ocular drug delivery
Sustained drug delivery is critical for patient adherence to chronic disease treatments. Here the authors apply machine learning to engineer multifunctional peptides with high melanin binding, high cell-penetration, and low cytotoxicity, enhancing the duration and efficacy of peptide-drug conjugates for sustained ocular delivery.
- Henry T. Hsueh
- , Renee Ti Chou
- & Laura M. Ensign
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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 AccessSmart thrombosis inhibitors without bleeding side effects via charge tunable ligand design
Treatments to prevent thrombosis are suboptimal. Here, the authors identify a lead an antithrombotic drug targeting polyphosphate based on switchable protonation states for the anion-binding groups, demonstrating antithrombotic activity in multiple mouse models, not causing bleeding, and well tolerated.
- Chanel C. La
- , Stephanie A. Smith
- & Jayachandran N. Kizhakkedathu
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Article
| Open AccessLow complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils
Here, the authors show the amyloid formation of a low-complexity domain of NCAP, and its potential for guiding the design of antiviral agents.
- Einav Tayeb-Fligelman
- , Jeannette T. Bowler
- & David S. Eisenberg
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Article
| Open AccessDisrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson’s disease
ESCRT-III is involved in the endolysosomal system and disturbed in neurodegenerative diseases. Here the authors show that disruption of an interaction between ESCRT-III member CHMP2B and α-synuclein by a peptide inhibitor mitigates neurodegeneration in Parkinson’s disease models.
- Satra Nim
- , Darren M. O’Hara
- & Philip M. Kim
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Article
| Open AccessEngineering tumor-specific gene nanomedicine to recruit and activate T cells for enhanced immunotherapy
Intratumoral abundance of chemokines, such as CXCL9, is an important driver of T cell infiltration in tumors. Here the authors describe the design of a tumor-specific expression strategy to drive secretion of CXCL9 and an anti-PD-L1 scFv (αPD-L1) in the tumor microenvironment, promoting T cell recruitment and anti-tumor immune response in preclinical cancer models.
- Yue Wang
- , Shi-Kun Zhou
- & Jun Wang
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Article
| Open AccessRNAi-mediated rheostat for dynamic control of AAV-delivered transgenes
Here the authors propose an RNA interference-based switch for dynamic control of AAV transgene expression. In this approach, transgene expression may be silenced by RNAi and subsequently recovered using REVERSIR oligonucleotides.
- Megha Subramanian
- , James McIninch
- & Vasant Jadhav
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Article
| Open AccessCollateral sensitivity profiling in drug-resistant Escherichia coli identifies natural products suppressing cephalosporin resistance
Collateral sensitivity (CS), whereby resistance to one drug is accompanied by increased sensitivity to another, provides new opportunities for antimicrobial drug discovery. Here, Liu et al. screen large chemical libraries across 29 drug-resistant E. coli strains to identify multiple CS interactions, including natural products with potent CS activities against cephalosporin-resistant strains.
- Dennis Y. Liu
- , Laura Phillips
- & Roger G. Linington
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Article
| Open AccessImproving the generalizability of protein-ligand binding predictions with AI-Bind
State-of-the-art machine learning models in drug discovery fail to reliably predict the binding properties of poorly annotated proteins and small molecules. Here, the authors present AI-Bind, a machine learning pipeline to improve generalizability and interpretability of binding predictions.
- Ayan Chatterjee
- , Robin Walters
- & Giulia Menichetti
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| Open AccessSafe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening
Authors propose their splenic mimetic filtration method, microsphiltration, and utilise this approach in a drug-screen, to identify compounds that induce a stiffening effect on Plasmodium falciparum-infected erythrocytes. They proceed to assess safety and tolerability of one identified compound in a phase I clinical trial.
- Mario Carucci
- , Julien Duez
- & Pierre Buffet
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| Open AccessCorrection of Clcn1 alternative splicing reverses muscle fiber type transition in mice with myotonic dystrophy
In a double homozygous mouse model of myotonic dystrophy type 1, Hu et al. use antisense oligonucleotide correction of myotonia to induce a therapeutic shift from an overabundance of oxidative muscle fibers to mechanically stronger glycolytic fibers.
- Ningyan Hu
- , Eunjoo Kim
- & Thurman M. Wheeler
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| Open AccessGenipin prevents alpha-synuclein aggregation and toxicity by affecting endocytosis, metabolism and lipid storage
In this work, the authors identify Genipin as a small iridoid able to prevent alpha-synuclein aggregation and toxicity by affecting endocytosis, metabolism and lipid storage.
- Rita Rosado-Ramos
- , Gonçalo M. Poças
- & Cláudia N. Santos
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Article
| Open AccessSingle-molecule fingerprinting of protein-drug interaction using a funneled biological nanopore
Efficient screening of protein-drug interactions (PDIs) has been impeded by the limitations of current biophysical approaches. Here, the authors present a funneled YaxAB nanopore sensor which allows label-free, single-molecule detection of proteins and PDIs.
- Ki-Baek Jeong
- , Minju Ryu
- & Seung-Wook Chi
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Article
| Open AccessNemacol is a small molecule inhibitor of C. elegans vesicular acetylcholine transporter with anthelmintic potential
Harrington et al report their discovery of Nemacol, which is a small molecule inhibitor of the vesicular acetylcholine transporter (VAChT). VAChT loads synaptic vesicles with acetylcholine and is a key point of vulnerability in animals. Harrington et al show that Nemacol has nematode selectivity and potential utility against nematode parasites.
- Sean Harrington
- , Jacob Pyche
- & Peter J. Roy
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| Open AccessPotent and selective covalent inhibition of the papain-like protease from SARS-CoV-2
The development of direct-acting antivirals to combat COVID-19 remains an important goal. Here the authors design covalent inhibitors that target the papain-like protease from SARS-CoV-2. The most promising inhibitor blocks viral replication in mammalian cells.
- Brian C. Sanders
- , Suman Pokhrel
- & Jerry M. Parks
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Article
| Open AccessP2X3 receptor antagonism attenuates the progression of heart failure
Despite medications, heart failure worsens with time with many patients dying within five years of diagnosis. Here the authors show that blocking purinergic receptors in the carotid body stops heart failure progression, improves its function, reduces sleep apneas and systemic inflammation in male rats.
- Renata M. Lataro
- , Davi J. A. Moraes
- & Julian F. R. Paton
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Article
| Open AccessTime-of-day defines NAD+ efficacy to treat diet-induced metabolic disease by synchronizing the hepatic clock in mice
The timing of NAD + supply determines its efficacy to treat metabolic disease. Here, the authors show that increasing NAD + at the early active phase maximizes weight loss and glucose regulation in mice. NAD + can displace the phase of the liver clock which can cause circadian misalignment.
- Quetzalcoatl Escalante-Covarrubias
- , Lucía Mendoza-Viveros
- & Lorena Aguilar-Arnal
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| Open AccessContinuous Spatiotemporal Therapy of A Full-API Nanodrug via Multi-Step Tandem Endogenous Biosynthesis
Nanomedicine is important in cancer therapy, but loading, drug release, and therapeutic effectiveness issues limit the translation to the clinic. Here, authors report a full-API nanodrug with an ideal API content and pH-responsive release for continuous spatiotemporal cancer therapy based on PpIX-heme-CO/Fe2+/BV-BR metabolic pathway.
- Fang Fang
- , Sa Wang
- & Jinfeng Zhang
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| Open AccessAn in-solution snapshot of SARS-COV-2 main protease maturation process and inhibition
The Main protease of SARS-CoV-2 is key for viral replication, but its maturation process is still not completely understood. Here, the authors not only reveal unique details from the first step of maturation, but also demonstrate how different classes of inhibitor can block this step.
- Gabriela Dias Noske
- , Yun Song
- & Andre Schutzer Godoy
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| Open AccessTrio-pharmacophore DNA-encoded chemical library for simultaneous selection of fragments and linkers
Dual-pharmacophore DNA-Encoded Libraries (DELs) can generate large libraries, but linker optimisation is challenging. Here, the authors report a trio-pharmacophore DEL (T-DEL) for both de novo fragment identification and linker optimization of known fragment pairs.
- Meiying Cui
- , Dzung Nguyen
- & Yixin Zhang
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Article
| Open AccessWavelength engineerable porous organic polymer photosensitizers with protonation triggered ROS generation
Engineering excitation wavelength of photosensitizers allows to enhanced reactive oxygen species but controlling the wavelength corresponding to operating conditions remains challenging. Here, the authors implement a wavelength-engineerable imidazolium-based porous organic polymer and demonstrate tuning of the optimal wavelength for maximum performance by modifying the linker system.
- Jinwoo Shin
- , Dong Won Kang
- & Chang Seop Hong
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Article
| Open AccessCRISPR-induced DNA reorganization for multiplexed nucleic acid detection
Nucleic acid sensing involving CRISPR technologies is powerful but has certain limitations, such as PAM sequence requirements and limited multiplexing. Here, authors report a CRISPR-based barcoding technology which enables multiple outputs from any target sequence, based on cis- and trans-cleavage.
- Margot Karlikow
- , Evan Amalfitano
- & Keith Pardee
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Article
| Open AccessStructural basis of selective cannabinoid CB2 receptor activation
Cannabinoid CB2 receptor (CB2R) agonists are investigated as therapeutic agents in the clinic. Here, authors report the discovery of LEI-102, a CB2R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate selective CB2R activation.
- Xiaoting Li
- , Hao Chang
- & Tian Hua
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Article
| Open Access1,2,4,5-Tetrazine-tethered probes for fluorogenically imaging superoxide in live cells with ultrahigh specificity
Specific detection of cellular superoxide is challenging. Here, the authors designed 1,2,4,5-tetrazine based fluorogenic probes for specific and sensitive imaging of superoxide, and applied them in high throughput screening of modulators of oxidative stress.
- Xuefeng Jiang
- , Min Li
- & Xin Li
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Article
| Open AccessReference compounds for characterizing cellular injury in high-content cellular morphology assays
Cellular nuisance compounds are a burden in chemical biology and drug screening. Here the authors profile prototypical cytotoxic and nuisance compounds using the cell painting assay to systematically characterise cellular morphologies associated with compound-dependent cellular injury and nuisance activity.
- Jayme L. Dahlin
- , Bruce K. Hua
- & Bridget K. Wagner
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| Open AccessAn anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity
The success of HER2-targeted cancer therapy is limited by treatment resistance. Here, the authors engineer an anti-HER2 biparatopic antibody with multiple mechanisms of action including induction of HER2 clustering to trigger complement dependent cytotoxicity, signal inhibition, antibody dependent cellular cytotoxicity and phagocytosis.
- Nina E. Weisser
- , Mario Sanches
- & Surjit Dixit
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Article
| Open AccessClinical and biomarker analyses of sintilimab plus gemcitabine and cisplatin as first-line treatment for patients with advanced biliary tract cancer
Chemotherapeutic agents and immune checkpoint inhibitors have shown modest efficacy in patients with advanced biliary tract cancers (BTCs). Here the authors report the results of a phase II trial of the anti-PD1 antibody sintilimab plus chemotherapy (gemcitabine and cisplatin) as first-line treatment for patients with advanced BTCs.
- Tian-mei Zeng
- , Guang Yang
- & Zhen-gang Yuan
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Article
| Open AccessMultiplexed analysis of EV reveals specific biomarker composition with diagnostic impact
Multiplexed analyses of near single EVs is currently challenging. Here the authors report the method MASEV, multiplexed analysis of EVs, to interrogate thousands of individual EVs during 5 cycles of multi-channel fluorescence staining for 15 EV biomarkers.
- Joshua D. Spitzberg
- , Scott Ferguson
- & Ralph Weissleder
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Article
| Open AccessTandem mass tag-based quantitative proteomic profiling identifies candidate serum biomarkers of drug-induced liver injury in humans
Diagnosis of rare, unpredictable, drug-induced liver injury (DILI) is a significant challenge for patients, clinicians, and drug development. Here, the authors discover, evaluate, and validate potential blood biomarkers to diagnose DILI and distinguish it from alternative causes of liver injury.
- Kodihalli C. Ravindra
- , Vishal S. Vaidya
- & Shashi K. Ramaiah
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Article
| Open AccessPredicting locations of cryptic pockets from single protein structures using the PocketMiner graph neural network
Cryptic pockets enable targeting of proteins currently considered undruggable because they lack pockets in their ground state structures. Here, the authors develop a graph neural network that accurately predicts cryptic pockets in static structures by training using molecular simulation data alone.
- Artur Meller
- , Michael Ward
- & Gregory R. Bowman
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Article
| Open AccessAutomatic and accurate ligand structure determination guided by cryo-electron microscopy maps
As cryo-EM becomes commonplace in drug discovery, tools for automating small molecule structure determination are needed. Here, authors show a map-guided ligand modeling approach to building ligand structures at resolutions common in cryo-EM.
- Andrew Muenks
- , Samantha Zepeda
- & Frank DiMaio
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Article
| Open AccessIdentification of SARS-CoV-2 Mpro inhibitors containing P1’ 4-fluorobenzothiazole moiety highly active against SARS-CoV-2
Effective antivirals are critical for combatting SARS-CoV-2 infections. Here, the authors develop two orally available small molecules, which specifically inhibit the activity of the SARS-CoV-2 main protease and potently block the infectivity and replication of various SARS-CoV-2 strains in cells and mice.
- Nobuyo Higashi-Kuwata
- , Kohei Tsuji
- & Hiroaki Mitsuya
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Article
| Open AccessMolecular imaging of liver inflammation using an anti-VCAM-1 nanobody
Here, the authors present a noninvasive tool to detect liver inflammation using nuclear imaging, as an alternative to biopsy. The prove the diagnostic power of this tool to detect liver inflammation in preclinical models of chronic liver disease.
- Maxime Nachit
- , Christopher Montemagno
- & Pascale Perret
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Article
| Open AccessASGARD is A Single-cell Guided Pipeline to Aid Repurposing of Drugs
The full potential of single-cell RNA-sequencing applied to precision medicine has yet to be reached. Here, we propose a drug recommendation system ASGARD, which predicts drugs by considering cell clusters to address the intercellular heterogeneity within each patient.
- Bing He
- , Yao Xiao
- & Lana X. Garmire
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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 AccessCross-protective antibodies against common endemic respiratory viruses
Immunocompromised patients are vulnerable to respiratory viral infections. Here, the authors characterize cross-neutralizing antibodies to respiratory syncytial virus, human metapneumovirus, and human parainfluenza viruses and show effective protection in male hamsters.
- Madelyn Cabán
- , Justas V. Rodarte
- & Jim Boonyaratanakornkit
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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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Article
| Open AccessAngiotensin-converting enzyme inhibitor promotes angiogenesis through Sp1/Sp3-mediated inhibition of notch signaling in male mice
ACE inhibitors are widely used to treat cardiovascular diseases and promote angiogenesis. Here, the authors show a central role for endothelial USP7-Sp1/Sp3-Notch1 signalling in pathophysiological angiogenesis in response to ACE inhibitor treatment.
- Hanlin Lu
- , Peidong Yuan
- & Wencheng Zhang
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Article
| Open AccessAccelerating inhibitor discovery for deubiquitinating enzymes
Deubiquitinases (DUBs) are key signaling enzymes, many of which lack selective inhibitors. Chan et al. pair a DUB-focused covalent library to mass spectrometry activity-based protein profiling, leading to selective hits against 23 endogenous DUBs and a first-in-class VCPIP1 probe with nanomolar potency.
- Wai Cheung Chan
- , Xiaoxi Liu
- & Sara J. Buhrlage
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Article
| Open AccessShark nanobodies with potent SARS-CoV-2 neutralizing activity and broad sarbecovirus reactivity
SARS-CoV-2 variants of concern continue to emerge, reducing vaccine efficacy and limiting therapeutic options. Here, Chen and colleagues describe the identification and design of shark nanobodies with pansarbecovirus activity.
- Wei-Hung Chen
- , Agnes Hajduczki
- & M. Gordon Joyce