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The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model
CAR and PXR receptors are known to regulate metabolism, however, there is no dual human ligand suitable for therapy. Here, the authors show a CAR agonist/PXR antagonist, MI-883, which regulates cholesterol/bile acid homeostasis by leveraging CAR and PXR activations in plasma cholesterol regulation.
- Jan Dusek
- , Ivana Mejdrová
- & Petr Pavek
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A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy
LYTAC strategies often face challenges in solid tumor penetration and synthesis. Here, the authors introduce Pep-TACs, a modular TFRC-based covalent peptide degradation platform that effectively degrades membrane protein PD-L1. This approach significantly suppresses both anti-PD-1-responsive and -resistant tumor growth, particularly in brain tumors.
- Youmei Xiao
- , Zhuoying He
- & Yanfeng Gao
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The oncolytic adenovirus TILT-123 with pembrolizumab in platinum resistant or refractory ovarian cancer: the phase 1a PROTA trial
TILT-123 is an oncolytic adenovirus encoding TNFα and IL-2. Here the authors report the results of a phase 1a trial of TILT-123 combined with anti-PD1 pembrolizumab in patients with platinum resistant or refractory ovarian cancer.
- Matthew Stephen Block
- , James Hugo Armstrong Clubb
- & Akseli Hemminki
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Structural basis for the ligand-dependent activation of heterodimeric AHR-ARNT complex
Aryl hydrocarbon receptor (AHR) is an emerging immune-related drug target. Here, the authors report the crystal structures of AHR with six agonists bound, revealing the molecular mechanisms of diverse ligand binding and allosteric activation of AHR.
- Xiaotong Diao
- , Qinghong Shang
- & Dalei Wu
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An abundant ginger compound furanodienone alleviates gut inflammation via the xenobiotic nuclear receptor PXR in mice
Here the authors discover that furanodienone (FDN), a small molecule derived from ginger, exhibits PXR agonist activity selective for the intestine and show that when FDN is administered orally in pharmacological doses ameliorates induced colitis in male mice.
- Xiaojuan Wang
- , Guohui Zhang
- & Jiabao Liu
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Methylcobalamin protects against liver failure via engaging gasdermin E
Gasdermin E (GSDME) is a pyroptotic cell death effector and a promising target for pyroptotic tissue injury. Here, the authors show that methylcobalamin in base-off conformation coordinates to Cys180 in GSDME to prevent caspase-3/GzmB-GSDME interactions and thereby GSDME-mediated liver failure.
- Wanfeng Xu
- , Yun Wang
- & Lijuan Cao
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Rescue RM/CS-AKI by blocking strategy with one-dose anti-myoglobin RabMAb
Myoglobin (Mb) is the critical pathogenic factor for Rhabdomyolysis or Crush syndrome-related AKI (RM/CS-AKI). Here, the authors show that anti-Mb RabMAb injection blocking the passage of free Mb through the glomerular filtration barrier significantly rescues both homologous and heterologous RM/CS-AKI animal models.
- Xinyue Wang
- , Ning Li
- & Yanhua Gong
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Supramolecular discrimination and diagnosis-guided treatment of intracellular bacteria
In this work, authors present a supramolecular fluorescent sensor array that enables the accurate discrimination of intracellular bacteria, also demonstrating that this can be modified as a host-guest drug delivery system to combat these bacteria.
- Jia-Hong Tian
- , Siyuan Huang
- & Dong-Sheng Guo
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Development and preclinical testing of a naloxone prodrug depot for extended protection against opioid overdose
The opioid antidote naloxone used to treat opioid overdoses has a short duration of action requiring repeated doses. Here the authors develop an extended release naloxone prodrug delivery system and report the preclinical testing in rat and cynomolgus monkey models.
- Hala Aldawod
- , Arjun D. Patel
- & Mamoun M. Alhamadsheh
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Barcoded screening identifies nanocarriers for protein delivery to kidney
The development of nanocarriers for targeted protein delivery requires methods for high-throughput screening in vitro and in vivo. Here authors develop a DNA-barcoded method to identify nanocarriers with different biodistributions, and demonstrate delivery of catalase to the kidneys of female mice, successfully mitigating cisplatin-induced acute kidney injury.
- Luyao Wang
- , Wen Zhou
- & Juanjuan Du
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Quantification and prediction of human fetal (-)-Δ9-tetrahydrocannabinol/(±)-11-OH-Δ9-tetrahydrocannabinol exposure during pregnancy to inform fetal cannabis toxicity
To determine causality between prenatal cannabis use and possible neurodevelopmental deficits, preclinical studies at relevant human fetal cannabinoid exposure must be conducted. Here the authors show these exposures which were successfully predicted by their maternal-fetal PBPK model.
- Aditya R. Kumar
- , Lyndsey S. Benson
- & Jashvant D. Unadkat
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Injectable supramolecular hydrogel co-loading abemaciclib/NLG919 for neoadjuvant immunotherapy of triple-negative breast cancer
The efficacy of cancer immunotherapy relies on the sufficient functional immune cells recruited. Here this group designs an abemaciclib-loaded supramolecular peptide hydrogel achieving sustained release after intratumoral injection to effectively induce cancer cell death and increase IL-2 secretion, thereby exerting immunotherapy for triple-negative breast cancer.
- Binyu Zhu
- , Ying Cai
- & Yaping Li
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Mutations to transcription factor MAX allosterically increase DNA selectivity by altering folding and binding pathways
In this work, high-throughput microfluidic assays reveal how allosteric substitutions that alter folding-and-binding pathways shape DNA specificity and selectivity landscapes in the human transcription factor MAX.
- Renee Hastings
- , Arjun K. Aditham
- & Polly M. Fordyce
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Intelligent in-cell electrophysiology: Reconstructing intracellular action potentials using a physics-informed deep learning model trained on nanoelectrode array recordings
Intracellular recording involves puncturing the cell membrane to gain access to the cell. In this work, the authors introduce a puncture-free intracellular recording approach that leverages a deep learning model to translate extracellular recordings into intracellular signals.
- Keivan Rahmani
- , Yang Yang
- & Zeinab Jahed
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Conformational diversity in class C GPCR positive allosteric modulation
Allosteric control of metabotropic glutamate receptor is of therapeutic value in the treatment of neurological disorders. Here, using cryoEM, the authors describe the diversity of positive allosteric modulation on the metabotropic glutamate receptor, mGlu5.
- Giuseppe Cannone
- , Ludovic Berto
- & Guillaume Lebon
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Chemical-guided SHAPE sequencing (cgSHAPE-seq) informs the binding site of RNA-degrading chimeras targeting SARS-CoV-2 5’ untranslated region
Highly structured RNA regions in SARS-CoV-2 serve as potential drug targets. Here the authors identified a class of small molecules binding to the 5’ UTR of the SARS-CoV-2 RNA genome. Using cgSHAPE-seq, they pinpointed a bulged G as the binding site and developed RNA-degrading chimeras that inhibit viral replication.
- Zhichao Tang
- , Shalakha Hegde
- & Jingxin Wang
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Methionine-driven methylation modification overcomes plasmid-mediated high-level tigecycline resistance
The dissemination of plasmid-encoded tigecycline resistance gene tet(X) poses a global threat to public health, necessitating the development of innovative strategies. Here, the authors reveal that the supplementation of L-methionine not only facilitates intracellular accumulation of tigecycline but also reduces tet(X) expression by augmenting the 5mC methylation modification in its promoter region, thereby overcoming plasmid-mediated high-level tigecycline resistance.
- Dan Fang
- , Tianqi Xu
- & Yuan Liu
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Design and application of synthetic 17B-HSD13 substrates reveals preserved catalytic activity of protective human variants
Several 17B-HSD13 variants have been identified as protective against NASH/MASH. However the protein’s endogenous function is unknown. Here authors describe sulfonamide-based inhibitors and synthetic substrates, then apply to multiple cellular systems revealing that the most prevalent IsoD variant maintains NAD-dependent catalytic activity.
- Michelle R. Garnsey
- , Yang Wang
- & Michelle F. Clasquin
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Small molecule APOL1 inhibitors as a precision medicine approach for APOL1-mediated kidney disease
Apolipoprotein L1 genetic variants contribute to a subtype of proteinuric kidney disease referred to as APOL1-mediated kidney disease (AMKD). Here the authors report the discovery and characterization of potent and selective APOL1 ion channel inhibitors for the potential treatment of AMKD.
- Brandon Zimmerman
- , Leslie A. Dakin
- & Mark E. Bunnage
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Robust proteome profiling of cysteine-reactive fragments using label-free chemoproteomics
This paper presents a label-free chemoproteomics platform using data-independent acquisition to profile covalent fragment binding across the human proteome. The platform offers high reproducibility and data completeness, identifying >400 protein-ligand interactions for probe development.
- George S. Biggs
- , Emma E. Cawood
- & Jacob T. Bush
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Enhanced motivated behavior mediated by pharmacological targeting of the FGF14/Nav1.6 complex in nucleus accumbens neurons
Protein/protein interaction (PPI) interfaces have emerged as drug targets to develop medications with less side effects. Here, Dvorak et al. show that small molecule targeting of PPIs in the brain is an approach for psychiatric drug discovery.
- Nolan M. Dvorak
- , Paul A. Wadsworth
- & Fernanda Laezza
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A new class of natural anthelmintics targeting lipid metabolism
Avocado fatty alcohols/acetates (AFAs) are effective against parasitic nematodes, including drug resistant strains, and show safety in mammalian cells. AFAs target lipid metabolism, offering the potential for new anthelmintic treatment pathways.
- Hala Zahreddine Fahs
- , Fathima S. Refai
- & Fabio Piano
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Structural insights into the regulation of monomeric and dimeric apelin receptor
The apelin receptor (APJR) is a drug target for cardiovascular and metabolic health. Here, authors reveal how ligand binding, receptor dimerization, and G protein coupling cooperate to regulate APJR signaling pathway, providing insight for drug discovery.
- Yang Yue
- , Lier Liu
- & Fei Xu
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Polysulfur-based bulking of dynamin-related protein 1 prevents ischemic sulfide catabolism and heart failure in mice
The oxidized glutathione (GSSG) has been considered as a marker of oxidative status. Here the authors show that GSSG, but not GSH, improves ischemic heart failure by inhibiting mitochondrial fission through polysulfur-based S-glutathionylation of Drp1 at Cys644.
- Akiyuki Nishimura
- , Seiryo Ogata
- & Motohiro Nishida
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A Bayesian active learning platform for scalable combination drug screens
Large-scale combination drug screens in cancer are extremely challenging because of the immense number of possible combinations. Here, the authors develop BATCHIE, a Bayesian active learning platform to design scalable and maximally informative drug combination screening assays; this is validated in retrospective and prospective cancer studies.
- Christopher Tosh
- , Mauricio Tec
- & Wesley Tansey
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Development of small molecule non-covalent coronavirus 3CL protease inhibitors from DNA-encoded chemical library screening
Due to the limited efficacy of vaccines against SARS-CoV-2 and resistance to current therapies additional anti-viral therapeutics with pan-coronavirus activity are of high interest. Here, the authors screened 2.8 billion compounds from a DNA-encoded chemical library and identified small molecules that are non-covalent inhibitors targeting the conserved 3CL protease of SARS-CoV-2 and other coronaviruses.
- Hengrui Liu
- , Arie Zask
- & Brent R. Stockwell
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Design of an equilibrative nucleoside transporter subtype 1 inhibitor for pain relief
In this study, Wrigth et al. use structural, medicinal chemistry, and behavioral approaches to examine how equilibrative nucleoside transporter subtype 1 (ENT1) exerts its functions; and their findings reveal ENT1 as a potential target for analgesia.
- Nicholas J. Wright
- , Yutaka Matsuoka
- & Seok-Yong Lee
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Neurotransmitter-bound bestrophin channel structures reveal small molecule drug targeting sites for disease treatment
Bestrophin anion channels are critical for the health of eyes. Here, authors identify multiple bestrophin activators including glutamate and γ-aminobutyric acid.
- Aaron P. Owji
- , Jingyun Dong
- & Tingting Yang
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An antibody cocktail targeting two different CD73 epitopes enhances enzyme inhibition and tumor control
The ectoenzyme CD73 is often elevated in tumour environments and targeting this protein is a tumour therapeutic target. Here the authors characterise a therapeutic anti-CD73 antibody cocktail which is more effective than either antibody alone and suggest a molecular mechanism of how this antibody cocktail functions.
- Jin-Gen Xu
- , Shi Chen
- & Li Wan
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Structural and functional determination of peptide versus small molecule ligand binding at the apelin receptor
This study explores apelin receptor’s role in cardiovascular function, identifying residues critical for binding through genetic variants, AlphaFold2 modelling and base editing in cardiomyocytes. Co-crystallization with biased agonist CMF-019 shows a unique binding mode versus endogenous peptides.
- Thomas L. Williams
- , Grégory Verdon
- & Anthony P. Davenport
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Structural mechanism of CB1R binding to peripheral and biased inverse agonists
Peripherally restricted CB1 inhibitors retain the weight loss benefits of this drug class while sparing the negative psychiatric side effects. The authors here elucidate cryo-EM structures of CB1 bound to peripherally restricted inhibitors to explain these drugs’ molecular mechanism of action.
- Punita Kumari
- , Szabolcs Dvorácskó
- & Daniel M. Rosenbaum
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Selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 as a rapid-acting therapy for advanced acute liver failure
Late-stage acute liver failure (ALF) has limited therapies. The authors show that the bioactive compound SCM-198 extends the ALF treatment window from 3 to 24 hours in mice by selectively targeting the identified AdipoR2-CaM-CaMKII-NOS3-NO axis.
- Rui Wang
- , Youwei Chen
- & Gufa Lin
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Development of a RIPK1 degrader to enhance antitumor immunity
It has been shown that targeting receptor-interacting protein kinase 1 (RIPK1) can improve response to immune checkpoint inhibitors. Here, using PROTAC technology, the authors report the design and characterization of a RIPK1 degrader, enhancing anti-tumor immunity in preclinical cancer models.
- Xin Yu
- , Dong Lu
- & Jin Wang
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Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM
Cellular target engagement technologies enable quantification of intracellular drug binding, but the simultaneous assessment of drug-associated phenotypes is challenging. Here, the authors develop CeTEAM (cellular target engagement by accumulation of mutant), a platform that can simultaneously evaluate drug-target interactions and phenotypic responses for holistic assessment of drug pharmacology using conditionally stabilized drug biosensors.
- Nicholas C. K. Valerie
- , Kumar Sanjiv
- & Mikael Altun
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Inhibition of ABCG2 prevents phototoxicity in a mouse model of erythropoietic protoporphyria
Erythropoietic protoporphyria is a genetic disease characterized by protoporphyrin IX-mediated painful phototoxicity. Here, the authors demonstrate that ABCG2 inhibitors can effectively prevent phototoxicity in a mouse model of erythropoietic protoporphyria.
- Junjie Zhu
- , Fu-Ying Qin
- & Xiaochao Ma
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γ-Glutamyl transpeptidase-activable nanoprobe crosses the blood-brain barrier for immuno-sonodynamic therapy of glioma
Chemotherapy of glioma is limited by delivering drugs across blood-brain barrier (BBB) to tumor sites in brain. Here, this group designs a neutrally-charged nanoprobe with γ-glutamyl moieties decorated on the surface that enabling the effective delivery of sonosensitizer and immune agonist R848 across BBB through adsorptive mediated transcytosis, thereby eliciting the anticancer effects.
- Bo Li
- , Gengjia Chen
- & Xintao Shuai
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Structural basis of orientated asymmetry in a mGlu heterodimer
Metabotropic glutamate receptors exist as both homo- and heterodimers. Here, the authors report the mGlu2-4 receptor structures in the inactive, intermediate and active states, and reveal the reason for the partial activity of the mono-liganded dimers.
- Weizhu Huang
- , Nan Jin
- & Jianfeng Liu
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Interformer: an interaction-aware model for protein-ligand docking and affinity prediction
Interformer, a generative deep learning model, enhances protein-ligand docking accuracy and generalizability by capturing essential non-covalent interactions. It demonstrates its practical value in real-world drug design by reasonably ranking ligand affinity through a contrastive learning strategy.
- Houtim Lai
- , Longyue Wang
- & Wei Liu
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Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19
In this work, the authors present novel PLpro inhibitors, with lead compound GZNL-P36 showing potent activity against SARS-CoV-2 variants, improving survival and reducing lung viral loads in a mouse model, offering promise for COVID−19 therapies.
- Yongzhi Lu
- , Qi Yang
- & Jinsai Shang
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ClickGen: Directed exploration of synthesizable chemical space via modular reactions and reinforcement learning
Generative models face challenges with low synthesizability of generated molecules. Here, authors develop ClickGen, a deep learning model using modular reactions and reinforcement learning to generate highly diverse, novel, and synthesizable molecules
- Mingyang Wang
- , Shuai Li
- & Chang-Yu Hsieh
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Single-cell encoded gene silencing for high-throughput combinatorial siRNA screening
Combined use of multiple siRNAs promises a new path for drug development. Here, the authors demonstrate a multiplexed combinatorial screening of thousands of siRNA formulations through highthroughput single-cell gene silencing, discovering the most effective anti-cancer siRNA cocktail therapeutics.
- Feng Guo
- , Xianglin Ji
- & Peng Shi
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Deep phenotypic profiling of neuroactive drugs in larval zebrafish
The authors used deep metric learning to characterize 650 neuroactive compounds by zebrafish behavioral profiles. After redesigning a large screen to overcome AI/ML shortcut learning, zebrafish behavioral similarity found compounds acting on the same human receptors as structurally dissimilar drugs.
- Leo Gendelev
- , Jack Taylor
- & Michael J. Keiser
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Genome-wide meta-analysis identifies 22 loci for normal tension glaucoma with significant overlap with high tension glaucoma
This study investigates the genetic similarities and differences between two subtypes of glaucoma (normal tension and high tension). Multi-ethnic meta-analysis reveals overlapping risk loci, with a lower effect magnitude in normal tension glaucoma. The authors also use their gene discovery approach to highlight possible neuro-protective drug targets for glaucoma.
- Santiago Diaz-Torres
- , Weixiong He
- & Puya Gharahkhani
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A non-canonical mechanism of GPCR activation
Ligands that activate GPCRs generally do so by stabilizing a particular conformation of the transmembrane helices. Here, the authors reveal a distinct activation mechanism where a ligand instead stabilizes a particular intracellular loop conformation.
- Alexander S. Powers
- , Aasma Khan
- & Ron O. Dror
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An allosteric inhibitor of RhoGAP class-IX myosins suppresses the metastatic features of cancer cells
This study reports adhibin, a synthetic carbazole that suppresses the migratory and adhesive properties of cancer cells by a mechanism of targeted RhoGAP class-IX myosin inhibition and selective RhoGTPase interference, both translating into migrastatic activity, opening other perspectives in cancer therapy and basic research.
- Despoina Kyriazi
- , Lea Voth
- & Georgios Tsiavaliaris
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Eliminating malaria transmission requires targeting immature and mature gametocytes through lipoidal uptake of antimalarials
Most compounds active against asexual blood stage malaria parasites show reduced activity against gametocytes. Here the authors directly compare asexual and gametocytocidal activity of 80 compounds and identify physicochemical properties that influence dual activity.
- Mariska Naude
- , Ashleigh van Heerden
- & Lyn-Marié Birkholtz
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Pharmacogenomic screening identifies and repurposes leucovorin and dyclonine as pro-oligodendrogenic compounds in brain repair
Effective treatments for myelin repair are currently lacking. Here, the authors show that two FDA-approved drugs, leucovorin and dyclonine, identified through pharmacogenomic screening, promote oligodendrocyte formation and brain repair in myelin injury models.
- Jean-Baptiste Huré
- , Louis Foucault
- & Carlos Parras
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Perspective
| Open AccessA framework for N-of-1 trials of individualized gene-targeted therapies for genetic diseases
Individualized genetic therapies present unique challenges for trial design. Here, the authors present a framework which emphasizes scientific rigor, using natural history, tailored clinical outcomes, and statistical considerations to optimize trial efficiency.
- Olivia Kim-McManus
- , Joseph G. Gleeson
- & Timothy Yu
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| Open Access
Label-free biosensor assay decodes the dynamics of Toll-like receptor signaling
Toll-like receptors are key mediators of immune responses, but gaps remain in understanding their signalling. Here, the authors introduce an optical biosensor assay to detect real-time TLR activation and signalling dynamics, uncovering signalling signatures that may aid future drug design.
- Janine Holze
- , Felicitas Lauber
- & Günther Weindl
Macrocycle-based PROTACs selectively degrade cyclophilin A and inhibit HIV-1 and HCV