Featured
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Article
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The CRISPR-Cas13a Gemini System for noncontiguous target RNA activation
CRISPR-Cas13a based methods currently use contiguous target RNA activation, which only enables single-target detection or editing. Here the authors propose a noncontiguous target RNA activation approach which can provide rapid, simultaneous and sensitive detection of two RNAs in a single readout, as well as parallel dual transgene knockdown.
- Hongrui Zhao
- , Yan Sheng
- & Jiaming Hu
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Article
| Open Access
VISTA checkpoint inhibition by pH-selective antibody SNS-101 with optimized safety and pharmacokinetic profiles enhances PD-1 response
VISTA is a pH-dependent inhibitory checkpoint for T-cells that is abundant on myeloid lineage cells and antagonists of VISTA may successfully reinvigorate anti-tumour immunity. Here, the authors show that the antibody SNS-101, which is currently being investigated in humans in a clinical trial, is characterized by pH-sensitivity that endows it with favorable pharmacokinetic and safety profiles, and enhanced therapeutic effect when combined with PD-1 checkpoint inhibitors.
- Thomas Thisted
- , F. Donelson Smith
- & Edward H. van der Horst
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Development and crystal structures of a potent second-generation dual degrader of BCL-2 and BCL-xL
Here, the authors have determined structures of 753b PROTAC, BCL-xL/BCL-2 and VHL E3 ligase ternary complexes which reveal the basis for the dual degrader activity of 753b. The structures and subsequent functional analyses facilitated design of WH244 PROTAC, with enhanced degrader activity in cells.
- Digant Nayak
- , Dongwen Lv
- & Shaun K. Olsen
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Article
| Open Access
Nanoparticles targeting mutant p53 overcome chemoresistance and tumor recurrence in non-small cell lung cancer
In non-small cell lung cancer (NSCLC), inactivating p53 mutations can drive resistance to cisplatin. Here, the authors develop fluplatin nanoparticles comprising a prodrug of cisplatin and fluvastin (mutant p53 inhibitor) which selectively degrades mutant p53, prevent tumor recurrences in preclinical models of p53 mutant NSCLC.
- Yu-Yang Bi
- , Qiu Chen
- & Hu-Lin Jiang
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Article
| Open Access
Methyl transfer in psilocybin biosynthesis
The natural hallucinogen psilocybin — produced by so-called magic mushrooms — holds promise for the treatment of depression and other mental health conditions. Here, the authors provide a structural and biochemical analysis of the Psilocybe methyl transferase PsiM that provides mechanistic insight into the last step of psilocybin biosynthesis.
- Jesse Hudspeth
- , Kai Rogge
- & Sebastiaan Werten
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Article
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A dual diffusion model enables 3D molecule generation and lead optimization based on target pockets
Structure-based generative chemistry is crucial in computer-aided drug discovery. Here, authors propose PMDM, a conditional generative model for 3D molecule generation tailored to specific targets. Extensive experiments demonstrate that PMDM can effectively generate rational bioactive molecules
- Lei Huang
- , Tingyang Xu
- & Hengtong Zhang
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Article
| Open Access
SNX8 enables lysosome reformation and reverses lysosomal storage disorder
Lysosomal storage disorders (LSDs) are severe genetic diseases currently without routine therapies. Here, the authors identified that SNX8 participates in lysosome reformation and serves as a potential drug target for new therapies to treat LSDs.
- Xinran Li
- , Cong Xiang
- & Xin-Hua Feng
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Article
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The binding and mechanism of a positive allosteric modulator of Kv3 channels
To promote the development of effective small molecule modulators that may help treat diverse neuropsychiatric disorders, this study elucidates the mechanism of a specific positive modulator of neuronal potassium channels at near-atomic resolution.
- Qiansheng Liang
- , Gamma Chi
- & Manuel Covarrubias
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Article
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Fibroblast-specific PRMT5 deficiency suppresses cardiac fibrosis and left ventricular dysfunction in male mice
Epigenetic mechanisms play a key role in cardiac fibrosis associated with heart failure. Here, the authors show that protein arginine methyltransferase 5 (PRMT5), an epigenetic writer, regulates fibrotic gene transcription through histone methylation in mice.
- Yasufumi Katanasaka
- , Harumi Yabe
- & Tatsuya Morimoto
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Article
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Filamentous fungus-produced human monoclonal antibody provides protection against SARS-CoV-2 in hamster and non-human primate models
The filamentous fungus expression system Thermothelomyces heterothallica (C1) is a protein expression system that may be useful for large scale antibody production. Here the authors characterise the production of a human monoclonal antibody that neutralises SARS-CoV-2 and compare functional properties in vitro and in animal models to antibodies produced using other methods.
- Franziska K. Kaiser
- , Mariana Gonzalez Hernandez
- & Albert D.M.E. Osterhaus
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Article
| Open Access
Inhibition of urease-mediated ammonia production by 2-octynohydroxamic acid in hepatic encephalopathy
Hepatic encephalopathy is a severe complication of liver disease with a growing prevalence. Here, the authors present a hydroxamate-based urease inhibitor to target the production of intestinal ammonia, one of the contributors to the pathogenesis of hepatic encephalopathy.
- Diana Evstafeva
- , Filip Ilievski
- & Jean-Christophe Leroux
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Article
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Homo-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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Specific pharmacological and Gi/o protein responses of some native GPCRs in neurons
G protein responses mediated by GPCRs may differ depending on their environment. Here, using highly sensitive Gi/o sensors, the authors reveal the specific pharmacological and Gi/o protein responses of some native GPCRs in neurons, and the influence of G protein composition.
- Chanjuan Xu
- , Yiwei Zhou
- & Jianfeng Liu
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Article
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A humanized mouse model for adeno-associated viral gene therapy
All natural AAV serotypes transduce murine hepatocytes more efficiently than their human counterparts in human liver chimeric mouse models. Here the authors developed a novel humanized mouse were human transduction of AAV can be studied.
- Mercedes Barzi
- , Tong Chen
- & Karl-Dimiter Bissig
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Article
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Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution
GPR109A is a prototypical GPCR and a key drug target for dyslipidemia. Here, the authors present cryo-EM structures of this receptor to elucidate agonist-binding and activation, and design receptor mutants with transducer-coupling-bias.
- Manish K. Yadav
- , Parishmita Sarma
- & Arun K. Shukla
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Article
| Open Access
Specificity, synergy, and mechanisms of splice-modifying drugs
Two small-molecule drugs, risdiplam and branaplam, have been developed for treating spinal muscular atrophy. Here the authors develop quantitative modeling methods for the sequence-specific and concentration-dependent effects of these and other splice-modifying drugs.
- Yuma Ishigami
- , Mandy S. Wong
- & Justin B. Kinney
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Article
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Drug target prediction through deep learning functional representation of gene signatures
Large-scale OMICs investigations of biological systems can be used to predict functional relationships between compounds, genes and proteins. Here, the authors develop a deep learning-based approach that significantly increases the number of high-quality compound-target predictions relative to existing methods.
- Hao Chen
- , Frederick J. King
- & Yingyao Zhou
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Perspective
| Open Access
Cellular reprogramming as a tool to model human aging in a dish
The development of human cellular models of aging that surpass the limitations of animal models of aging is urgent. Here, the authors explore the opportunities and limitations of cellular reprogramming to create reliable aging in vitro models and their potential for the discovery of anti-aging compounds.
- Patricia R. Pitrez
- , Luis M. Monteiro
- & Lino Ferreira
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Targeting 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 Access
Transfer learning with graph neural networks for improved molecular property prediction in the multi-fidelity setting
Modern molecular discovery processes generate millions of measurements at different quality levels. Here, the authors develop a new deep learning method for transfer learning from low-cost and abundant data to enhance the efficiency of drug discovery.
- David Buterez
- , Jon Paul Janet
- & Pietro Lió
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Article
| Open Access
Design 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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Perspective
| Open Access
Annexins—a family of proteins with distinctive tastes for cell signaling and membrane dynamics
Annexins are calcium-regulated membrane binding proteins with an array of cellular activities. Here, Gerke et al. describe recent research highlighting the many functions of annexins and provide a view on directions for the future.
- Volker Gerke
- , Felicity N. E. Gavins
- & Ursula Rescher
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Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies
The T cell receptor β-chain is expressed in two isoforms, TRBC1 and TRBC2, with clonally expanded mature T cell lymphomas expressing one of them exclusively, while healthy T cells randomly express either TRBC1 or TRBC2. Here authors show structure-based design of a TRBC2-specific antibody, and depletion of malignant T cells carrying TRBC1 or TRBC2 with CAR-T cells against the cognate receptor chain in murine models.
- Mathieu Ferrari
- , Matteo Righi
- & Martin Pule
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Article
| Open Access
Learning representations for image-based profiling of perturbations
Assessing cell phenotypes in image-based assays requires solid computational methods for transforming images into quantitative data. Here, the authors present a strategy for learning representations of treatment effects from high-throughput imaging, following a causal interpretation.
- Nikita Moshkov
- , Michael Bornholdt
- & Juan C. Caicedo
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Article
| Open Access
Structural optimization of siRNA conjugates for albumin binding achieves effective MCL1-directed cancer therapy
Limited tumor cell delivery is a major challenge for the efficacious delivery of siRNAs to silence traditionally undruggable oncogenes. Here the authors optimize siRNAs for in situ binding to albumin through C18 lipid modifications and show the application of the lead conjugate structure for targeting MCL1 in orthotopic breast tumors in mice.
- Ella N. Hoogenboezem
- , Shrusti S. Patel
- & Craig L. Duvall
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Article
| Open Access
Cepharanthine analogs mining and genomes of Stephania accelerate anti-coronavirus drug discovery
Cepharanthine is a secondary metabolite isolated from Stephania with a variety of medicinal properties. Here, the authors assembled three Stephania genomes, propose cepharanthine biosynthetic pathway, and assess the antiviral potential of cepharanthine-related metabolites.
- Liang Leng
- , Zhichao Xu
- & Shilin Chen
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Article
| Open Access
Cyclic 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 Access
Leukemic 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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Modeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip
Here the authors develop perfusable inner blood-retinal barrier-specific microvascular networks with human primary retinal microvascular cells. They show that chronic diabetic stimulation leads to the generation of early hallmarks of diabetic retinopathy, including pericyte and capillary dropout, ghost vessels, and inflammation.
- Thomas L. Maurissen
- , Alena J. Spielmann
- & Héloïse Ragelle
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Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor
There is a need for effective antiviral drugs against RSV infection. Conducting an RSV repurposing screen using the ReFRAME library Sake et al. identify lonafarnib as an RSV fusion protein inhibitor, characterize its binding site within the viral protein and show its antiviral effects in a mouse model.
- Svenja M. Sake
- , Xiaoyu Zhang
- & Thomas Pietschmann
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| Open Access
Structural 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
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Regulating protein corona on nanovesicles by glycosylated polyhydroxy polymer modification for efficient drug delivery
The dynamic protein corona hinders the uptake of nanocarriers in desired target cell populations, limiting their bench-to-bedside translation. Here the authors reveal that the modification of hydroxyl and amino functional groups on nanovesicles can rationally regulate the composition of protein coronas to improve the efficiency of targeted drug delivery.
- Yunqiu Miao
- , Lijun Li
- & Yong Gan
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Article
| Open Access
Antiviral fibrils of self-assembled peptides with tunable compositions
In this work, the authors report the use of a computationally and rationally designed self-assembling peptide that has robust antiviral capability with demonstrated specificity in binding to SARS-CoV-2 and inhibition of viral entry into human cells.
- Joseph Dodd-o
- , Abhishek Roy
- & Vivek Kumar
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Article
| Open Access
AAV-delivered muscone-induced transgene system for treating chronic diseases in mice via inhalation
Long-term control of therapeutic transgene expression is needed. Here the authors report a muscone-induced transgene system packaged into AAVs based on a G protein-coupled murine olfactory receptor and a synthetic cAMP-responsive promoter: they show dose- and exposure-time-dependent gene expression control in mice.
- Xin Wu
- , Yuanhuan Yu
- & Haifeng Ye
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Article
| Open Access
DynamicBind: predicting ligand-specific protein-ligand complex structure with a deep equivariant generative model
Proteins often function by changing conformations upon ligand binding. Efficient structural modelling of these interactions, crucial for drug discovery, is limited: here the authors address this with DynamicBind, a diffusion-based deep generative model.
- Wei Lu
- , Jixian Zhang
- & Shuangjia Zheng
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Article
| Open Access
CDK6 inhibits de novo lipogenesis in white adipose tissues but not in the liver
Obesity is a risk factor for diseases. Here, authors found that inhibition of cyclin-dependent kinase 6 increased de novo lipogenesis in the adipose tissues but not in the liver, which may provide a strategy to concur obesity-induced maladies.
- Alexander J. Hu
- , Wei Li
- & Miaofen G. Hu
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Article
| Open Access
Artesunate treats obesity in male mice and non-human primates through GDF15/GFRAL signalling axis
Obesity is a global health challenge with an ongoing need for new medical treatments. Here, the authors show that artesunate, an FDA-approved treatment for severe malaria, can be repurposed for the treatment of obesity via GDF15/GFRAL signaling axis without overt side effects in mice and non-human primates.
- Xuanming Guo
- , Pallavi Asthana
- & Hoi Leong Xavier Wong
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Article
| Open Access
Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase
New antimalarials are urgently needed. Here, the authors identify Open Source Malaria compound, OSMS-106, as a reaction hijacking inhibitor of the malaria parasite protein synthesis machinery, with potential use for treatment and prophylaxis.
- Stanley C. Xie
- , Yinuo Wang
- & Leann Tilley
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Article
| Open Access
Elucidation of unusual biosynthesis and DnaN-targeting mode of action of potent anti-tuberculosis antibiotics Mycoplanecins
Mycoplanecins show promising activity against tuberculosis. Here, the authors identify and study mycoplanecins’ biosynthesis, antibacterial effects, and binding mechanism to DnaN, suggesting potential for fighting multidrug-resistant tuberculosis.
- Chengzhang Fu
- , Yunkun Liu
- & Rolf Müller
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Article
| Open Access
Discovery 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 Access
High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia
Using an unbiased phenotypic cell-based high-throughput screen, the authors identify and characterize a small molecule, BCH-HSP-C01, that restores aberrant protein trafficking in neuronal models of adapter protein complex 4 deficiency.
- Afshin Saffari
- , Barbara Brechmann
- & Mustafa Sahin
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Article
| Open Access
Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines
Here, the authors describe a potent and selective CK1a molecular glue degrader with a broad antiproliferative potency. Crystallographic data provide rationale for the high degradation efficacy displayed by this compound.
- Gisele Nishiguchi
- , Lauren G. Mascibroda
- & Zoran Rankovic
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Article
| Open Access
Design-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 Access
Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors
The serotonin transporter, targeted by several medications, terminates neurotransmission by clearing serotonin from the synaptic cleft. Combining biochemical results with in silico data, the authors show the key interactions that initiate substrate transport.
- Ralph Gradisch
- , Katharina Schlögl
- & Thomas Stockner
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Article
| Open Access
Inhibition of iRhom1 by CD44-targeting nanocarrier for improved cancer immunochemotherapy
A pro-tumorigenic role of iRhom1 has been described in several cancer types. Here the authors show that iRhom1 regulates sensitivity to chemotherapy and immune response, as well they report that CD44 targeting nanoparticle-mediated co-delivery of iRhom1 pre-siRNA promotes anti-tumor immune responses in preclinical cancer models.
- Zhangyi Luo
- , Yixian Huang
- & Song Li
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Article
| Open Access
Molecular mechanism of antihistamines recognition and regulation of the histamine H1 receptor
Histamine receptor H1R has been extensively targeted in the development of antihistamines. Here, Wang et al. determine structures of H1R alone and bound to different antihistamines, providing insights into the structure-based design of next-generation drugs.
- Dandan Wang
- , Qiong Guo
- & Yuyong Tao
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Article
| Open Access
A nanoemulsion targeting adipose hypertrophy and hyperplasia shows anti-obesity efficiency in female mice
Adipose tissue enlargement involves adipose hyperplasia and hypertrophy, which correlate with excessive ROS and hyperactivated XBP1. Here, the authors introduce KT-NE, a nanoemulsion combining KIRA6 (an XBP1 inhibitor) and α-Tocopherol, easing ER and oxidative stress in (pre)adipocytes and showing anti-obesity effectiveness.
- Yichao Lu
- , Zhenyu Luo
- & Lihua Luo
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Article
| Open Access
Avapritinib-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 Access
Multiplexed multicolor antiviral assay amenable for high-throughput research
Antiviral approaches against entire genera or families of viruses need to be constantly developed and innovated. Focusing on several distantly-related orthoflaviviruses, the authors develop a cell-based multiplex antiviral assay for high-throughput screening against multiple viruses at once.
- Li-Hsin Li
- , Winston Chiu
- & Kai Dallmeier
A chemical proteomics approach for global mapping of functional lysines on cell surface of living cell