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Article
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A 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 Access
Investigation of monoclonal antibody CSX-1004 for fentanyl overdose
Fentanyl continues to drive the opioid crisis by contributing to >70,000 deaths per year in the US. Here, the authors investigate a candidate medication for fentanyl overdose prevention (monoclonal antibody CSX-1004) demonstrating its mitigation of fentanyl’s effects in preclinical animal models.
- Paul T. Bremer
- , Emily L. Burke
- & Rajeev I. Desai
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Article
| Open Access
A multi-reservoir extruder for time-resolved serial protein crystallography and compound screening at X-ray free-electron lasers
Protein serial crystallography at X-ray free-electron lasers (XFELs) is a powerful technique for structure determination. Here, authors present a device for sample delivery designed to abate challenges to non-specialists allowing for compound screening.
- Maximilian Wranik
- , Michal W. Kepa
- & Jörg Standfuss
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Article
| Open Access
CurveCurator: a recalibrated F-statistic to assess, classify, and explore significance of dose–response curves
Dose-response curves are ubiquitous in pharmacology and biology, yet potency and effect size are often estimated even when there is no response. Here, authors present a statistical framework to assess curve significance and demonstrate how this aids drug mode of action analysis in large public datasets.
- Florian P. Bayer
- , Manuel Gander
- & Matthew The
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Matters Arising
| Open AccessHow carvedilol does not activate β2-adrenoceptors
- Robert J. Lefkowitz
- , Howard A. Rockman
- & Milton Packer
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Article
| Open Access
Explainable machine learning for profiling the immunological synapse and functional characterization of therapeutic antibodies
Therapeutic antibodies are crucial in treating severe diseases. Here, the authors introduce scifAI, an open-source explainable AI framework for analyzing imaging flow cytometry data, enabling rapid screening of therapeutic antibody candidates.
- Sayedali Shetab Boushehri
- , Katharina Essig
- & Fabian Schmich
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Article
| Open Access
NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson’s disease
Oral nicotinamide riboside (NR) at a dose of 3000 mg daily for 30 days is safe and associated with a pronounced systemic augmentation of the NAD metabolome, but no methyl donor depletion.
- Haakon Berven
- , Simon Kverneng
- & Charalampos Tzoulis
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Article
| Open Access
Evaluation of circulating plasma proteins in breast cancer using Mendelian randomisation
Proteomics of blood samples is a promising avenue for cancer diagnosis. Here, the authors conduct Mendelian randomisation analysis of protein levels across multiple cohorts, and identify 5 proteins that show promise as biomarkers for the long-term risk of breast cancer, and as potential drug targets.
- Anders Mälarstig
- , Felix Grassmann
- & Åsa K. Hedman
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Article
| Open Access
Discovery of a novel cardiac-specific myosin modulator using artificial intelligence-based virtual screening
Modulation of the myosin molecular motor has emerged as a potential therapeutic target for both heart disease and heart failure. Here, the authors use AI-based virtual high throughput screening to identify compounds that acts as a cardiac-specific myosin modulators.
- Priyanka Parijat
- , Seetharamaiah Attili
- & Thomas Kampourakis
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Article
| Open Access
A knowledge-guided pre-training framework for improving molecular representation learning
Accurate property prediction relies on effective molecular representation. Here, the authors introduce KPGT, a knowledge-guided self-supervised framework that improves molecular representation, leading to superior predictions of molecular properties and advancing AI-driven drug discovery.
- Han Li
- , Ruotian Zhang
- & Jianyang Zeng
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Article
| Open Access
A semiconductor 96-microplate platform for electrical-imaging based high-throughput phenotypic screening
Cell-based phenotypic assays link in vitro discovery to disease pathology. Here, the authors report a semiconductor-based microplate platform to perform high-throughput, high-dimensional “electrical imaging” for label-free assessment of live cell morphology and function.
- Shalaka Chitale
- , Wenxuan Wu
- & Jeffrey Abbott
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Article
| Open Access
Targeting ferroptosis by poly(acrylic) acid coated Mn3O4 nanoparticles alleviates acute liver injury
Ferroptosis is involved in the pathogenesis of several human diseases and targeted inhibition of ferroptosis is promising for their clinical treatment. Here, the authors report the synthesis of ultrasmall poly(acrylic) acid coated Mn3O4 nanoparticles that can act as mimics of antioxidant enzymes and scavenge reactive oxygen species, as well as potently suppress ferroptosis.
- Xinyi Shan
- , Jiahuan Li
- & Hao Wu
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Article
| Open Access
Small molecule regulators of microRNAs identified by high-throughput screen coupled with high-throughput sequencing
Regulatory miRNAs have significant therapeutic potential. Here the authors developed a screen to identify small molecule drugs that modulate miRNome profiles in human neurons and validated cardiac glycosides as inducers of the neuroprotective miR-132.
- Lien D. Nguyen
- , Zhiyun Wei
- & Anna M. Krichevsky
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Article
| Open Access
Wireless, battery-free, multifunctional integrated bioelectronics for respiratory pathogens monitoring and severity evaluation
The SARS-CoV-2 pandemic highlighted our need for methods that allow rapid viral surveillance. Here, authors report a wireless, battery-free and wearable self-diagnosis platform that can continuously capture viral particles, diagnose infection status and evaluate symptom severity via breath and blow.
- Hu Li
- , Huarui Gong
- & Xinge Yu
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Article
| Open Access
CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade
TAK-931 is a selective CDC7 inhibitor and can induce replication stress (RS)-mediated chromosomal instability with antitumoral activity. Here the authors show that TAK-931-induced RS generates aneuploid cells with an inflammatory phenotype, rendering tumors sensitive to immune-checkpoint blockade.
- Tomoko Yamamori Morita
- , Jie Yu
- & Akihiro Ohashi
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Article
| Open Access
Sequence-based prediction of the intrinsic solubility of peptides containing non-natural amino acids
Posttranslationally modified amino acids are crucial in physiology and drug development as they alter physicochemical properties such as the solubility of proteins. Here the authors describe CamSolPTM, a software that accurately predicts the solubility of proteins containing these residues.
- Marc Oeller
- , Ryan J. D. Kang
- & Michele Vendruscolo
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Article
| Open Access
Simultaneous selection of nanobodies for accessible epitopes on immune cells in the tumor microenvironment
INSPIREseq discovers accessible epitopes in complex environments and leads to nanobodies targeting thousands of epitopes. This in vivo diversity selection identifies selective nanobodies, potentially expediting target discovery and drug development.
- Thillai V. Sekar
- , Eslam A. Elghonaimy
- & Todd A. Aguilera
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Article
| Open Access
Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson’s disease mouse model
USP30 has been proposed to regulate mitophagy, a relevant Parkinson’s disease mechanism. Here, the authors show that Usp30 knockout mice and USP30 inhibitors like MTX115325 demonstrate neuroprotective responses in an alpha-synuclein mouse model of Parkinson’s disease.
- Tracy-Shi Zhang Fang
- , Yu Sun
- & David K. Simon
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Article
| Open Access
CLOOME: contrastive learning unlocks bioimaging databases for queries with chemical structures
Artificial intelligence can assist in obtaining knowledge from bioimaging data, but need human annotation. Here the authors use multimodal contrastive learning to link chemical structures and cell phenotypes, which can lead to foundation models for microscopy images.
- Ana Sanchez-Fernandez
- , Elisabeth Rumetshofer
- & Günter Klambauer
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Article
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Enhanced pericyte-endothelial interactions through NO-boosted extracellular vesicles drive revascularization in a mouse model of ischemic injury
Treatment alternatives are not available for a significant portion of critical limb ischemia patients. Here, the authors show a strategy to engineer mesenchymal stem cells-derived extracellular vesicles to induce revascularization in mice.
- Ling Guo
- , Qiang Yang
- & Min Feng
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Article
| Open Access
A large meta-analysis identifies genes associated with anterior uveitis
Anterior Uveitis is a common inflammatory eye disease that can result in vision loss. Here, the authors perform GWAS and whole-exome analyses of Anterior Uveitis to identify the underlying genetics of HLA-B*27 positive and negative forms of the disease.
- Sahar Gelfman
- , Arden Moscati
- & Giovanni Coppola
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Article
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Bifunctionality 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 Access
Mechanism of selective recognition of Lys48-linked polyubiquitin by macrocyclic peptide inhibitors of proteasomal degradation
Macrocyclic peptides were recently discovered as potent modulators of ubiquitin-mediated cellular signaling pathways. Here the authors used multidisciplinary approach to uncover how macrocyclic peptides that inhibit proteasomal degradation selectively recognize long Lys48-linked polyubiquitin chains.
- Betsegaw Lemma
- , Di Zhang
- & David Fushman
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Article
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A generative adversarial network model alternative to animal studies for clinical pathology assessment
Generative AI has the potential to transform the way chemical and drug safety research is conducted. Here the authors show AnimalGAN, a model developed using Generative Adversarial Networks, which simulates virtual animal experiments to generate multidimensional rat clinical pathology measurements.
- Xi Chen
- , Ruth Roberts
- & Weida Tong
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Article
| Open Access
A randomised Phase IIa trial of amine oxidase copper-containing 3 (AOC3) inhibitor BI 1467335 in adults with non-alcoholic steatohepatitis
The authors report data from a Phase IIa randomised, double-blind trial in patients with NASH showing that BI 1467335 strongly and dose-dependently inhibited AOC3 activity (involved in hepatic inflammation) and was well tolerated at all tested doses.
- Philip N. Newsome
- , Arun J. Sanyal
- & Eric Lawitz
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Article
| Open Access
Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin
Therapeutic modulation of Janus kinase family enzymes is an established approach for inflammatory and autoimmune skin diseases. Here the authors rationally design small interfering RNAs to enable single Janus kinase targeting and test this new therapeutic approach in a skin disease model for maintaining efficacy and improving selectivity.
- Qi Tang
- , Hassan H. Fakih
- & John E. Harris
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Article
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Recognition and reprogramming of E3 ubiquitin ligase surfaces by α-helical peptides
Identification of molecules that induce novel interactions between proteins has been limited by the complexity of rationally designing interactions. The authors report a method to discover molecular glue-like “trimerizers” based on α-helically constrained peptides that can co-opt the surfaces of E3 ubiquitin ligases to bind therapeutically important proteins.
- Olena S. Tokareva
- , Kunhua Li
- & John H. McGee
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Article
| Open Access
Cyclic fasting bolsters cholesterol biosynthesis inhibitors’ anticancer activity
Nutritional stress induced by short-term dietary restriction has been shown to alter the activity of some anti-tumour drugs. Here, the authors demonstrate that periodic fasting enhances the anti-tumour effect of cholesterol biosynthesis inhibitors via decreased AKT-STAT3 signaling and oxidative phosphorylation.
- Amr Khalifa
- , Ana Guijarro
- & Alessio Nencioni
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Article
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A 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
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Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation
CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia progress. Here the authors show that homodimer-mediated phosphorylation of C/EBPα-p42 modulates acute myeloid leukaemia cell differentiation by liquid-liquid phase separation.
- Dongmei Wang
- , Tao Sun
- & Chunyan Ji
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Article
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Near-infrared-II photoacoustic imaging and photo-triggered synergistic treatment of thrombosis via fibrin-specific homopolymer nanoparticles
The near-infrared-II (NIR-II) window has shown great promise for in vivo imaging and therapy. Here, the authors integrate a homopolymer and thermo-sensitive nitric oxide prodrug into nanoparticles for long-wavelength NIR-II photoacoustic imaging and synergistic treatment in preclinical thrombosis models.
- Jianwen Song
- , Xiaoying Kang
- & Ji Qi
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Article
| Open Access
Lipid nanoparticles with PEG-variant surface modifications mediate genome editing in the mouse retina
There is a need for development of efficient delivery vehicles for the treatment of inherited retinal degeneration with gene therapy. Here, Gautam et al., show that surface modifications of lipid nanoparticles with PEG variants alters their cellular tropism allowing gene editing in diverse retinal cell types in mice.
- Milan Gautam
- , Antony Jozic
- & Gaurav Sahay
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Article
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A 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 Access
ZSP1601, a novel pan-phosphodiesterase inhibitor for the treatment of NAFLD, A randomized, placebo-controlled phase Ib/IIa trial
Non-alcoholic fatty liver disease is a growing health burden with limited treatment options worldwide. Herein the authors report a randomized, double-blind, placebo-controlled, multiple-dose trial of a first-in-class pan-phosphodiesterase inhibitor ZSP1601 in NAFLD patients.
- Yue Hu
- , Haijun Li
- & Yanhua Ding
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Article
| Open Access
Revealing invisible cell phenotypes with conditional generative modeling
Biological research relies on observing cell phenotypes, often obscured by natural variability. Here, the authors use generative modelling to unveil hidden changes triggered by infections, mutations, or drugs, allowing for accessible discovery of biomarkers.
- Alexis Lamiable
- , Tiphaine Champetier
- & Auguste Genovesio
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Article
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Structure-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 Access
A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models
β-cell dysfunction in type 2 diabetes is associated with pathological aggregates of IAPP that accumulate in pancreatic islets. Here, the authors describe a novel antibody cloned from healthy elderly donors that selectively targets IAPP oligomers and protects from IAPP toxicity.
- Fabian Wirth
- , Fabrice D. Heitz
- & Jan Grimm
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Article
| Open Access
A 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 Access
Myoglobin-loaded gadolinium nanotexaphyrins for oxygen synergy and imaging-guided radiosensitization therapy
Researchers have been working on radiosensitizers to improve radiotherapy efficacy. Here the authors generate gadolinium nanotexaphyrins (Gd-NTs) that self-assemble and further load it with myoglobulin to relieve hypoxia, improve radiosensitization effects of Gd-coordinated Texaphyrin, and suppress tumor recurrence.
- Xiaotu Ma
- , Xiaolong Liang
- & Fan Wang
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Perspective
| Open Access
The uncertain role of substandard and falsified medicines in the emergence and spread of antimicrobial resistance
Substandard and falsified medicines are a problem, particularly in low- and middle-income countries, and effects on antimicrobial resistance development aren’t well understood. Here, the authors discuss mechanisms by which they can increase or decrease levels of resistance and the need for improved data collection and analytical approaches.
- Sean Cavany
- , Stella Nanyonga
- & Ben S. Cooper
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Article
| Open Access
Development of cyclopeptide inhibitors of cGAS targeting protein-DNA interaction and phase separation
Cyclic GMP-AMP synthase (cGAS) is critical in modulating cellular inflammation. Here, the authors report a class of cyclopeptide inhibitors of cGAS targeting protein DNA interaction and phase separation.
- Xiaoquan Wang
- , Youqiao Wang
- & Junmin Quan
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Article
| Open Access
Targeting 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 Access
A common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators
A common East Asian-specific defect of an alcohol metabolizing enzyme (ALDH2) causes glucose abnormality, obesity, and fatty liver. Here, the authors show an ALDH2 activator can treat these metabolic disorders in mice.
- Yi-Cheng Chang
- , Hsiao-Lin Lee
- & Lee-Ming Chuang
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Article
| Open Access
A subset of type-II collagen-binding antibodies prevents experimental arthritis by inhibiting FCGR3 signaling in neutrophils
Rheumatoid arthritis (RA) involves several types of autoantibodies, which are usually considered pathogenic. In this study, the authors use phage display to develop antibodies targeting type-II collagen that are protective in multiple experimental models of RA.
- Zhongwei Xu
- , Bingze Xu
- & Rikard Holmdahl
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Comment
| Open Access
Breaking barriers for glioblastoma with a path to enhanced drug delivery
Progress in treatment for glioblastoma is hindered by the blood-brain barrier (BBB). In genetic mouse models recapitulating brain invasion and abnormal angiogenesis of human glioblastoma, Cai and colleagues demonstrate that optical modulation of the BBB with nanoparticles boosts intratumoural chemotherapy concentration, prolonging survival. We discuss prospects for clinical translation of exemplary innovative techniques.
- Imran Noorani
- & Jorge de la Rosa
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Article
| Open Access
Telomerase RNA-based aptamers restore defective myelopoiesis in congenital neutropenic syndromes
The RNA component telomerase (TERC) has a critical non-canonical role in the formation of the myeloid lineage. Here, the authors show aptamers that mimic the behaviour of the entire TERC molecule in myelopoiesis activation.
- Elena Martínez-Balsalobre
- , Jesús García-Castillo
- & María L. Cayuela
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Article
| Open Access
Chronic cough relief by allosteric modulation of P2X3 without taste disturbance
P2X3 activation requires tightening the inner pocket of the head domain (IP-HD) following ATP binding. Here the authors demonstrate that targeting the IP-HD with allosteric small molecules presents a potential strategy for the development of therapeutics for refractory chronic cough without taste abnormalities.
- Chang-Run Guo
- , Zhong-Zhe Zhang
- & Ye Yu
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Article
| Open Access
Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection
TANK-binding kinase-1 (TBK1) and its homologue IκB kinase-ε (IKKε) are critical in the induction of the interferon response and the response to infection by pathogens. Here the authors show that pharmacological targeting of TBK1 AND IKKε reduces the immunopathology seen in a murine model of SARS-COV-2 infection.
- Tomalika R. Ullah
- , Matt D. Johansen
- & Michael P. Gantier
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Article
| Open Access
Discovery and pharmacophoric characterization of chemokine network inhibitors using phage-display, saturation mutagenesis and computational modelling
Ticks inject evasins at the bite site to bind multiple redundant chemokines and inhibit inflammation allowing blood feeding. Here, the authors identify evasin derived short peptides with broad spectrum anti-chemokine activity that could be used to develop new treatments for inflammatory disease.
- Serena Vales
- , Jhanna Kryukova
- & Shoumo Bhattacharya
A lung-selective delivery of mRNA encoding broadly neutralizing antibody against SARS-CoV-2 infection