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| Open AccessTargeted sampling of natural product space to identify bioactive natural product-like polyketide macrolides
Polyketide macrolides are of interest for drug discovery but their inherent structural and stereochemical complexity hinders the exploration of related regions of chemical space more broadly. Here, the authors designed in silico and synthesized a library of tetrahydrofuran-containing polyketide macrolides, and screened them against a panel of biological assays, identifying biologically active library members.
- Darryl M. Wilson
- , Daniel J. Driedger
- & Robert A. Britton
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Article
| Open AccessBioengineered amyloid peptide for rapid screening of inhibitors against main protease of SARS-CoV-2
The main protease (Mpro) plays a crucial role in the replication of SARS-CoV-2, thereby making it an attractive target for COVID-19 treatment. Here, the authors develop a colorimetric screening platform for discovering Mpro inhibitors using engineered amyloid peptide-based nanocomplexes.
- Dongtak Lee
- , Hyo Gi Jung
- & Dae Sung Yoon
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Article
| Open AccessHomo-BacPROTAC-induced degradation of ClpC1 as a strategy against drug-resistant mycobacteria
Antimicrobial resistance is a global health threat and the development of alternative strategies to overcome it is of high interest. Here, the authors report proteolysis targeting chimeras active in bacteria (BacPROTACs) that bind to ClpC1, a component of the mycobacterial protein degradation machinery, and apply them for targeting a range of mycobacterial strains, including antibiotic-resistant ones.
- Lukas Junk
- , Volker M. Schmiedel
- & Guido Boehmelt
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Article
| Open AccessDesign of target specific peptide inhibitors using generative deep learning and molecular dynamics simulations
Here the authors report a computational approach which integrates deep learning and structural modelling to design target-specific peptides. They apply this to β-catenin and NF-κB essential modulator, resulting in improved binding, highlighting the efficacy of this strategy.
- Sijie Chen
- , Tong Lin
- & Xiaolin Cheng
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Article
| Open AccessCyclic peptides discriminate BCL-2 and its clinical mutants from BCL-XL by engaging a single-residue discrepancy
Pro-survival B-cell lymphoma-2 (BCL-2) family proteins BCL-2 and BCL-XL are the targets of anti-tumour drugs, but resistance is emerging. The authors present cyclic peptides against BCL-2 and BCL-XL, with a distinct mechanism of targeting characterised.
- Fengwei Li
- , Junjie Liu
- & Dalei Wu
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Article
| Open AccessStructural basis for lysophosphatidylserine recognition by GPR34
GPR34 is a GPCR which has an immunomodulatory role and recognizes lysophosphatidylserine (LysoPS) as a putative endogenous ligand. Here, authors report two cryo-EM structures of human GPR34-Gi complex with one of two ligands bound: either the LysoPS analogue S3E-LysoPS, or its derivative M1.
- Tamaki Izume
- , Ryo Kawahara
- & Osamu Nureki
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Article
| Open AccessSQM2.20: Semiempirical quantum-mechanical scoring function yields DFT-quality protein–ligand binding affinity predictions in minutes
The paper presents the universal QM-based scoring function that accurately and rapidly predicts protein-ligand binding affinities, outperforming current computational tools. This is demonstrated on the PL-REX experimental benchmark dataset.
- Adam Pecina
- , Jindřich Fanfrlík
- & Jan Řezáč
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Article
| Open AccessTotal syntheses of Tetrodotoxin and 9-epiTetrodotoxin
Tetrodotoxin and congeners are specific voltage-gated sodium channel blockers that exhibit remarkable anesthetic and analgesic effects but total synthesis procedures are often limited by the scale. Here, the authors present a scalable asymmetric syntheses of Tetrodotoxin and 9-epiTetrodotoxin from the abundant chemical feedstock furfuryl alcohol.
- Peihao Chen
- , Jing Wang
- & Xiangbing Qi
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Article
| Open AccessDiscovery of a peripheral 5HT2A antagonist as a clinical candidate for metabolic dysfunction-associated steatohepatitis
Metabolic Dysfunction-Associated Steatohepatitis (MASH), an advanced form of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), can progress to liver fibrosis. Here, the authors develop a peripheral 5HT2A antagonist for the treatment of MASLD and MASH.
- Haushabhau S. Pagire
- , Suvarna H. Pagire
- & Jin Hee Ahn
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Article
| Open AccessPredictive Minisci late stage functionalization with transfer learning
Regioselectivity prediction for many reactions remains a challenging target for a priori prediction. Here, the authors develop a machine learning model that predicts the outcomes of Minisci reactions.
- Emma King-Smith
- , Felix A. Faber
- & Alpha A. Lee
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Article
| Open AccessDesign-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists
Stapled α-helical peptides are promising for targeting challenging targets such as transcription factors, but achieving sufficient cell permeability while avoiding off-target cleavage is difficult. Here, the authors present workflows for identifying stapled peptides against Mdm2(X) with in vivo activity and no off-target effects based on comprehensive investigations of their properties.
- Arun Chandramohan
- , Hubert Josien
- & Anthony W. Partridge
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Article
| Open AccessAvapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA
Avapritinib, a potent inhibitor, offers hope for D842V-mutant GIST patients with high response rates; however, resistance and side effects remain challenges. Here, crystal structures shed light on this and reveal a Gα-pocket for drug development.
- A. Teuber
- , T. Schulz
- & D. Rauh
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Article
| Open AccessDirect-to-biology, automated, nano-scale synthesis, and phenotypic screening-enabled E3 ligase modulator discovery
Targeted protein degradation (TPD) is an emerging therapeutic that can lead to proteasomal degradation of target proteins. Here, the authors combine nano-scale, automated synthesis and cell-based, direct-to-biology screening, allowing them to discover and profile Molecular Glues (MGs) degrading substrates via the Cereblon E3 ubiquitin ligase.
- Zefeng Wang
- , Shabnam Shaabani
- & Alexander Dömling
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Article
| Open AccessIdentification of 5-HT2A receptor signaling pathways associated with psychedelic potential
Serotonin 5-HT2A receptor signaling mechanisms associated with predicting psychedelic potential remain elusive. Using 5-HT2A-selective β-arrestin-biased ligands, here the authors show that a threshold level of 5-HT2A-Gq efficacy and not β-arrestin recruitment is associated with psychedelic potential.
- Jason Wallach
- , Andrew B. Cao
- & John D. McCorvy
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Article
| Open AccessLate-stage synthesis of heterobifunctional molecules for PROTAC applications via ruthenium-catalysed C‒H amidation
PROTACs are uniquely powerful therapeutic agents, but their synthetic tractability significantly limit drug discovery programs. Here, the authors developed a single step synthesis of PROTAC conjugates via late stage ruthenium-catalysed C–H amidation.
- Daniele Antermite
- , Stig D. Friis
- & Magnus J. Johansson
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Article
| Open AccessNear-infrared light-triggered prodrug photolysis by one-step energy transfer
Prodrug photolysis enables spatiotemporal control of drug release at the desired lesions, but most of the photocleavable groups cannot be directly activated by near-infrared (NIR) light that features deep penetration and low phototoxicity. Here, the authors report an upconversion-like process via only one step of energy transfer for NIR light-triggered prodrug photolysis.
- Kaiqi Long
- , Wen Lv
- & Weiping Wang
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Article
| Open AccessA monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence
Chemotherapy-induced peripheral neuropathy (CIPN) represents a major reason for discontinuation of treatment. Here, the authors show that LEI-515, a peripherally restricted monoacylglycerol lipase inhibitor, suppresses CIPN without inducing central nervous system side effects or physical dependence.
- Ming Jiang
- , Mirjam C. W. Huizenga
- & Mario van der Stelt
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Article
| Open AccessDiscovery of a Drug-like, Natural Product-Inspired DCAF11 Ligand Chemotype
Targeted protein degradation (TPD) has emerged as a new paradigm for modulating protein activity. Here, the authors develop bifunctional degraders combining a putative ligand of the autophagy-related LC3 protein with different protein targets, which direct proteins of interest to the proteasome by covalently targeting the DCAF11 E3 ligase substrate receptor.
- Gang Xue
- , Jianing Xie
- & Herbert Waldmann
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Article
| Open AccessModular access to alkylgermanes via reductive germylative alkylation of activated olefins under nickel catalysis
While carbon-introducing difunctionalization of C-C double bonds is well established, the analogous difunctionalization for introducing germanium group and other functionalities remains elusive. Here, the authors describe a nickel-catalyzed germylative alkylation of activated olefins with easily accessible primary, secondary and tertiary alkyl bromides and chlorogermanes as the electrophiles to form C-Ge and C-Calkyl bonds simultaneously.
- Rui Gu
- , Xiujuan Feng
- & Xuan Zhang
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Article
| Open AccessBifunctionality of dirhodium tetracarboxylates in metallaphotocatalysis
Traditional metallaphotocatalysis often requires two or more separate catalysts and is considered to be costly and not tolerant towards a wide substrate scope. Here the authors realize metallaphotocatalysis with a bifunctional dirhodium tetracarboxylate as single catalyst component to merge carbenoid chemistry and 1O2 chemistry.
- Taoda Shi
- , Tianyuan Zhang
- & Wenhao Hu
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Article
| Open AccessSelective activator of human ClpP triggers cell cycle arrest to inhibit lung squamous cell carcinoma
Chemo-activation of mitochondrial ClpP exhibits promising anticancer properties. Here, the authors develop a potent activator ZK53 that is highly selective on human ClpP but inactive toward bacterial ClpP proteins, and show that ZK53 causes cell cycle arrest via ClpP on lung squamous cell carcinoma cells and exhibits therapeutic effects in animal models.
- Lin-Lin Zhou
- , Tao Zhang
- & Cai-Guang Yang
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Comment
| Open AccessLimitations of representation learning in small molecule property prediction
Machine learning is a powerful tool for the study and design of molecules. Here the authors comment a recent publication in Nature Communications which highlights the challenges of different molecular representations for data-driven property predictions.
- Ana Laura Dias
- , Latimah Bustillo
- & Tiago Rodrigues
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Article
| Open AccessA systematic study of key elements underlying molecular property prediction
AI has become a crucial tool for drug discovery, but how to properly represent molecules for data-driven property prediction is still an open question. Here the authors evaluate 62,820 models to highlight existing challenges, the impact of activity cliffs, and the crucial role of dataset size.
- Jianyuan Deng
- , Zhibo Yang
- & Fusheng Wang
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Article
| Open AccessCatalytic 4-exo-dig carbocyclization for the construction of furan-fused cyclobutanones and synthetic applications
Aromatic ring fused cyclobutanone is a strained motif with broad applications. Here, the authors report a catalytic 4- exo-dig process, which proved successful to access furan-fused cyclobutanones that can serve as versatile synthetic blocks.
- Kemiao Hong
- , Yi Zhou
- & Xinfang Xu
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Article
| Open AccessStructure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2
SH2 domains are challenging to target using small molecules. Here, the authors develop phosphotyrosine-based covalent ligands of the E3 ligase SOCS2 using structure-based design. A pro-drug approach yields cell active inhibitors that block SOCS2 substrate recruitment.
- Sarath Ramachandran
- , Nikolai Makukhin
- & Alessio Ciulli
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Article
| Open AccessA pharmacophore-guided deep learning approach for bioactive molecular generation
Designing novel molecules with desired bioactivity is a critical challenge in drug discovery, particularly for novel or understudied targets. The authors propose a pharmacophore-guided deep learning approach PGMG to generate diverse active-like molecules with limited activity data.
- Huimin Zhu
- , Renyi Zhou
- & Min Li
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Article
| Open AccessCatalytic enantioselective reductive alkynylation of amides enables one-pot syntheses of pyrrolidine, piperidine and indolizidine alkaloids
Saturated α-alkyl aza-heterocycles are found in a wide array of bioactive molecules. Here, the authors disclosed a one-pot, catalytic enantioselective synthesis of pyrrolidine, piperidine and indolizidine alkaloids from amides and alkynes.
- Fang-Fang Xu
- , Jin-Quan Chen
- & Pei-Qiang Huang
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Article
| Open AccessRetrosynthesis prediction with an interpretable deep-learning framework based on molecular assembly tasks
Automating retrosynthesis prediction in organic chemistry is a major application of ML. Here the authors present RetroExplainer, which offers a high-performance, transparent and interpretable deep-learning framework providing valuable insights for drug development.
- Yu Wang
- , Chao Pang
- & Leyi Wei
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Article
| Open Access2-Oxabicyclo[2.2.2]octane as a new bioisostere of the phenyl ring
The phenyl ring is a basic structural element in chemistry. Here, the authors show the design, synthesis, and validation of 2-oxabicyclo[2.2.2]octane as a new saturated bioisostere with improved physicochemical properties
- Vadym V. Levterov
- , Yaroslav Panasiuk
- & Pavel K. Mykhailiuk
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Article
| Open AccessTargeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs
In this work, the authors report a drug class based on an ancient innate defense fold. Inspired by Nature’s anti-infective strategies, this peptide-based drug targets systemic inflammation via multiple molecular interactions, enhancing effectiveness
- Ganna Petruk
- , Manoj Puthia
- & Artur Schmidtchen
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Article
| Open AccessAn amide to thioamide substitution improves the permeability and bioavailability of macrocyclic peptides
Solvent shielding of the amide hydrogen bond donor through chemical modification or conformational control has been successfully utilized to impart membrane permeability to macrocyclic peptides. Here, the authors show that passive membrane permeability can also be conferred by masking the amide hydrogen bond acceptor through thioamide substitution, leading to improved pharmacological properties of peptide macrocycles.
- Pritha Ghosh
- , Nishant Raj
- & Jayanta Chatterjee
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Article
| Open AccessFirst fully-automated AI/ML virtual screening cascade implemented at a drug discovery centre in Africa
Streamlined data-driven drug discovery remains challenging, especially in resource-limited settings. Here, the authors present ZairaChem, an AI/ML tool that streamlines QSAR/QSPR modelling, implemented for the first time at the H3D Centre in South Africa.
- Gemma Turon
- , Jason Hlozek
- & Miquel Duran-Frigola
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Article
| Open AccessA Bischler-Napieralski and homo-Mannich sequence enables diversified syntheses of sarpagine alkaloids and analogues
The Mannich reaction is a well-established method for the synthesis of β-amino carbonyl compounds while the analogous reactions of homo-enol or its equivalents with imines or iminium ions are much less explored. Here, the authors describe a homo-Mannich reaction of cyclopropanol with imines generated via a Bischler-Napieralski reaction.
- Hanyue Qiu
- , Xinghai Fei
- & Min Zhang
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Article
| Open AccessDiscovery of a selective and biologically active low-molecular weight antagonist of human interleukin-1β
Interleukin-1β is a pro-inflammatory cytokine of medical importance. Here the authors describe the discovery of a low-molecular weight compound that antagonizes hIL-1β function in cells, demonstrating the relevance of this discovery for future development of hIL-1β directed therapeutics.
- Ulrich Hommel
- , Konstanze Hurth
- & Frédéric Bornancin
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Article
| Open AccessAll-round catalytic and atroposelective strategy via dynamic kinetic resolution for N-/2-/3-arylindoles
While a variety of well-established methods enable the control of a stereogenic center, a catalytic method for controlling a stereogenic axis in one substrate is typically unavailable for controlling axial chirality in other substrates with a similar structure. Here, the authors report o-amidobiaryl as a flexible platform for chiral phosphoric acid catalyzed atroposelective dynamic kinetic resolution.
- Ahreum Kim
- , Chanhee Lee
- & Yongseok Kwon
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Article
| Open AccessIdentification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts
Developing selective N-myristoyltransferase (NMT) inhibitors has been challenging. Here, the authors describe selective NMT inhibitors that can be used as multistage antimalarials, targeting dormant and developing forms of liver and blood stage.
- Diego Rodríguez-Hernández
- , Kamalakannan Vijayan
- & Morten Grøtli
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Article
| Open AccessDivergent access to 5,6,7-perifused cycles
The lack of efficient and diverse synthesis strategy has hindered the study of perifused cycles. Here, the authors report a metal-catalyzed cascade electrocyclization to access 5,6,7-perifused cycles, and demonstrated the versatility of this protocol in the late-stage modification of pharmaceuticals.
- Jingpeng Han
- , Yongjian Yang
- & Baosheng Li
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Article
| Open AccessStructural basis of lipid-droplet localization of 17-beta-hydroxysteroid dehydrogenase 13
Hydroxysteroid 17-beta-dehydrogenase 13 (HSD17B13) is a hepatic lipid droplet-associated enzyme that is upregulated in patients with non-alcoholic fatty liver disease. Here, the authors report crystal structures of HSD17B13 and its complexes with two series of inhibitors.
- Shenping Liu
- , Ruth F. Sommese
- & Michelle F. Clasquin
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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 AccessDiversity-oriented synthesis encoded by deoxyoligonucleotides
Most DNA-encoded library (DEL) syntheses are limited by the presence of sensitive DNA-based constructs. Here, the authors develop DOSEDO, a diverse 3.7 million compound DEL, generated through diversity-oriented synthesis that provides enhanced scaffold and exit vector diversity and gives validated binding hits for multiple protein targets.
- Liam Hudson
- , Jeremy W. Mason
- & Karin Briner
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Article
| Open AccessSmall molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels
Branched chain ketoacid dehydrogenase kinase (BDK) inhibits the activity of branched chain ketoacid dehydrogenase and branched chain amino acid degradation, implicated in several diseases. Here, the authors discover a BDK inhibitor and degrader that shows efficacy in rodent metabolism and heart failure models, as well as another class of BDK inhibitors that stabilizes BDK.
- Rachel J. Roth Flach
- , Eliza Bollinger
- & Kevin J. Filipski
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Article
| Open AccessMacrocyclization of linear molecules by deep learning to facilitate macrocyclic drug candidates discovery
Macrocyclization of bioactive acyclic molecules provides a potential avenue to yield novel chemical scaffolds with improved pharmacological properties. Here, the authors propose a deep learning based macrocyclization method to generate diverse macrocycles from a given acyclic molecule.
- Yanyan Diao
- , Dandan Liu
- & Honglin Li
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Article
| Open AccessDNA framework-engineered chimeras platform enables selectively targeted protein degradation
The lack of a universal platform for PROTAC development remains a major bottleneck. Here, the authors report modular DNA framework-based PROTACs (DbTACs) that enable precise control of the linker length and selective degradation of diverse targets in different cellular compartments using various warheads.
- Li Zhou
- , Bin Yu
- & Yi Ma
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Article
| Open AccessHypoRiPPAtlas as an Atlas of hypothetical natural products for mass spectrometry database search
A gap exists between large-scale genome mining and mass spectral datasets for natural product discovery. Here the authors bridge the gap by developing HypoRiPPAtlas, an Atlas of hypothetical natural product structures, which is ready-to-use for in silico database search of tandem mass spectra.
- Yi-Yuan Lee
- , Mustafa Guler
- & Hosein Mohimani
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Article
| Open AccessRapid planning and analysis of high-throughput experiment arrays for reaction discovery
High-throughput experimentation is an increasingly important tool in reaction discovery, while there remains a need for software solutions to navigate data-rich experiments. Here the authors report phactor™, a software that facilitates the performance and analysis of high-throughput experimentation in a chemical laboratory.
- Babak Mahjour
- , Rui Zhang
- & Tim Cernak
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Article
| Open AccessNon-covalent inhibitors of thioredoxin glutathione reductase with schistosomicidal activity in vivo
Only praziquantel is available for treating schistosomiasis, a disease affecting >200 million people. Here, the authors identify compounds active against schistosome infections meeting the criteria for lead progression indicated by WHO with better activity against juvenile worms than praziquantel.
- Valentina Z. Petukhova
- , Sammy Y. Aboagye
- & Pavel A. Petukhov
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Article
| Open AccessUSP25 regulates KEAP1-NRF2 anti-oxidation axis and its inactivation protects acetaminophen-induced liver injury in male mice
The redox status of a cell is regulated through a number of mechanisms, chief among these is the KEAP1-mediated ubiquitination and degradation of NRF2. Here the authors show that KEAP1 itself is ubiquitinated and degraded in a process that is opposed by the ubiquitin-specific protease USP25.
- Changzhou Cai
- , Huailu Ma
- & Jiewei Wang
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Review Article
| Open AccessRadiochemistry for positron emission tomography
Positron emission tomography is widely used to diagnose and monitor different disease states and interest in the technique has led to the demand for the development of new method for radiolabelling. Here the authors review the recent progress in the development of new PET probes.
- Jian Rong
- , Ahmed Haider
- & Steven H. Liang
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Article
| Open AccessDevelopment of allosteric and selective CDK2 inhibitors for contraception with negative cooperativity to cyclin binding
Despite the therapeutic interest in targeting CDK2, developing a selective CDK2 inhibitor has been challenging. Here, the authors describe a potent and selective CDK2 inhibitor that binds an allosteric pocket, preventing activating protein partners from binding and showing potential as a contraceptive.
- Erik B. Faber
- , Luxin Sun
- & Gunda I. Georg