Featured
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| Open AccessHigh-throughput small molecule screen identifies inhibitors of microsporidia invasion and proliferation in C. elegans
Microsporidia are fungal-related intracellular parasites that infect animals and humans. Here, Murareanu et al. develop a high-throughput screening method using the nematode C. elegans as a host, and identify several compounds that inhibit microsporidia infection through different mechanisms.
- Brandon M. Murareanu
- , Noelle V. Antao
- & Aaron W. Reinke
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Article
| Open AccessIdentification of a binding site on soluble RANKL that can be targeted to inhibit soluble RANK-RANKL interactions and treat osteoporosis
Huang et al. discover a binding site on soluble RANKL that is not found on its membrane-bound homologue. A drug screening identified a small molecule (S3-15) that can target this binding site and has anti-osteoporotic but not immunosuppressive effects.
- Dane Huang
- , Chao Zhao
- & Jun Xu
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| Open AccessCombi-seq for multiplexed transcriptome-based profiling of drug combinations using deterministic barcoding in single-cell droplets
Current screens to assess tumour drug resistance require a large amount of material, normally not available from patients. Here the authors report CombiSeq, a scalable microfluidic workflow to screen hundreds of drug combinations in picoliter-size droplets using transcriptome changes as a readout.
- L. Mathur
- , B. Szalai
- & C. A. Merten
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Article
| Open AccessLow-cost anti-mycobacterial drug discovery using engineered E. coli
Whole-cell screening for Mycobacterium tuberculosis inhibitors is complicated by the pathogen’s slow growth and biocontainment requirements. Here the authors develop engineered E. coli as a synthetic biology tool to express and screen metabolic targets from Mycobacterium tuberculosis.
- Nadine Bongaerts
- , Zainab Edoo
- & Edwin H. Wintermute
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Article
| Open AccessSynthesis and direct assay of large macrocycle diversities by combinatorial late-stage modification at picomole scale
Macrocycles have potential as therapeutics, but their libraries are currently not large enough for high-throughput screening. Here, the authors show a combinatorial approach to generate a library of almost 20’000 macrocycles by conjugating carboxylic-acid fragments to macrocyclic scaffolds, identifying nanomolar inhibitors against thrombin and binders of MDM2.
- Sevan Habeshian
- , Manuel Leonardo Merz
- & Christian Heinis
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Article
| Open AccessTargeting fungal membrane homeostasis with imidazopyrazoindoles impairs azole resistance and biofilm formation
There is an urgent need for novel strategies to combat life-threatening fungal infections. Here, Revie et al. identify a compound that induces alterations in fungal membranes, synergizes with azole antifungals against the pathogen Candida albicans, and inhibits virulence traits and biofilm formation in animal models of infection.
- Nicole M. Revie
- , Kali R. Iyer
- & Leah E. Cowen
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Article
| Open AccessThe drug-induced phenotypic landscape of colorectal cancer organoids
The heterogeneity underlying cancer organoid phenotypes is not yet well understood. Here, the authors develop an imaging analysis assay for high throughput phenotypic screening of colorectal organoids that allows to define specific morphological changes that occur following different drug treatments.
- Johannes Betge
- , Niklas Rindtorff
- & Michael Boutros
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Article
| Open AccessMutational signatures are markers of drug sensitivity of cancer cells
Mutational signatures can reveal the impact of mutagenic processes in cancer, including exposure to therapy. Here, the authors develop an approach that can accurately predict drug responses in cancer using mutational signatures while simultaneously correcting for germline variants with an ancestry matching procedure.
- Jurica Levatić
- , Marina Salvadores
- & Fran Supek
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Article
| Open AccessIntegrated profiling of human pancreatic cancer organoids reveals chromatin accessibility features associated with drug sensitivity
The chromatin accessibility landscape and gene regulatory network of pancreatic cancer has not been fully characterised. Here, the authors perform multi-omics analysis of 84 pancreatic cancer organoid lines and reveal gene regulatory networks and distinct molecular subtypes.
- Xiaohan Shi
- , Yunguang Li
- & Dong Gao
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Article
| Open AccessIntegrative multi-omics and drug response profiling of childhood acute lymphoblastic leukemia cell lines
Childhood acute lymphoblastic leukemia is characterised by a range of genetic aberrations. Here, the authors use multi-omics profiling of ALL cell lines to connect molecular phenotypes and drug responses to provide an interactive resource of drug sensitivity.
- Isabelle Rose Leo
- , Luay Aswad
- & Rozbeh Jafari
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Article
| Open AccessTranscriptional repression of estrogen receptor alpha by YAP reveals the Hippo pathway as therapeutic target for ER+ breast cancer
Hippo signalling is reported to be required for proper ESR1 expression. Here the authors reveal that the transcriptional repression of ESR1 is via LATS-YAP-TEAD-VGLL3 axis and the epigenetic regulation of ESR1 super enhancer in ER + breast cancer.
- Shenghong Ma
- , Tracy Tang
- & Kun-Liang Guan
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Article
| Open AccessQuinacrine-CASIN combination overcomes chemoresistance in human acute lymphoid leukemia
Chemoresistance and relapse are main limitations in the treatment of acute lymphoblastic leukemia (ALL). Here, the authors identify Quinacrine (QC) as a sensitizer for Cytarabine (AraC) and establish a QC-CASIN regimen to improve leukemia eradication in ALL.
- Limei Wu
- , Srinivas Chatla
- & Wei Du
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Article
| Open AccessRepurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission
Lack of expression and function of chloride ion-extruding transporter KCC2 in central neurons, a consequence of various forms of neural injury, is strongly suggested to contribute to chronic pain. Here the authors identify from a screen of cancer drugs a kinase-inhibitor, kenpaullone, as an enhancer of Kcc2/KCC2 gene expression and show that it (i) alleviates pain like behaviour in animal models, (ii) repairs neural-circuit disrupting elevated chloride in pain relay neurons in the dorsal spinal cord.
- Michele Yeo
- , Yong Chen
- & Wolfgang Liedtke
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Article
| Open AccessSmall-molecule suppression of calpastatin degradation reduces neuropathology in models of Huntington’s disease
Mitochondrial dysfunction is a common hallmark of neurological disorders. Here, the authors identify CHIR99021 as a potent enhancer of mitochondrial function, which improved mitochondrial phenotypes in Huntington’s disease models. CHIR99021 was shown to stabilize calpastatin, which suppressed calpain activation and Drp1-induced mitochondrial fragmentation.
- Di Hu
- , Xiaoyan Sun
- & Xin Qi
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Article
| Open AccessImproved modeling of human AD with an automated culturing platform for iPSC neurons, astrocytes and microglia
Human induced pluripotent stem cell (iPSC) cells have been used to model disease in specific cell types. Here, the authors develop an automated long-term culturing platform of human iPSC neurons, astrocytes, and microglia and use it to model some cellular aspects of Alzheimer’s disease.
- Reina Bassil
- , Kenneth Shields
- & Ben Chih
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Article
| Open AccessIntegration of FRET and sequencing to engineer kinase biosensors from mammalian cell libraries
Existing Förster Resonance Energy Transfer (FRET) biosensors are often limited in their sensitivity. Here the authors report FRET-seq which they use to identify Fyn and ZAP70 kinase biosensors with enhanced performance, and use them to image T-cell activation and screen drugs.
- Longwei Liu
- , Praopim Limsakul
- & Yingxiao Wang
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Article
| Open AccessA high-throughput screen for TMPRSS2 expression identifies FDA-approved compounds that can limit SARS-CoV-2 entry
The serine protease TMPRSS2 primes SARS-CoV-2 glycoprotein for cell entry. Here, the authors perform a screen to identify drugs that reduce TMPRSS2 expression and find that halofuginone modulates proteasome-mediated degradation of TMPRSS2 and reduces entry of SARS-CoV-2.
- Yanwen Chen
- , Travis B. Lear
- & Bill B. Chen
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Article
| Open AccessDrug repurposing screens identify chemical entities for the development of COVID-19 interventions
Here, the authors perform repurposing screens of the ReFRAME drug library in two cell lines and identify inhibitors of SARS-CoV-2 infection. Antiviral activity of prodrug MK-4482 is confirmed in hamsters.
- Malina A. Bakowski
- , Nathan Beutler
- & Thomas F. Rogers
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Article
| Open AccessMolecular landscape and subtype-specific therapeutic response of nasopharyngeal carcinoma revealed by integrative pharmacogenomics
Nasopharyngeal carcinoma (NPC) is a malignant cancer type with high morbidity in Asia, and its current molecular classification is insufficient to predict therapy outcomes. Here the authors explore NPC subtype-specific response to therapy with a pharmacogenomics strategy integrating genomics and drug response of patient-derived organoids.
- Ren-Bo Ding
- , Ping Chen
- & Chu-Xia Deng
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| Open AccessCharacterization of an engineered live bacterial therapeutic for the treatment of phenylketonuria in a human gut-on-a-chip
Engineered live bacteria could represent a new class of therapeutic treatment for human disease. Here, the authors use a human gut-on-a-chip microfluidics system to characterize an engineered live bacterial therapeutic, designed for the treatment of phenylketonuria, and to construct mathematical models that predict therapeutic strain function in non-human primates.
- M. Tyler Nelson
- , Mark R. Charbonneau
- & Camilla A. Mauzy
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Article
| Open AccessEpigenetic modulation reveals differentiation state specificity of oncogene addiction
Epigenetic mechanisms associated with the differentiation state of cancer cells and their heterogeneity influence tumor responses to oncogene-targeted therapies. In this study, the authors perform an epigenetic compound screen and single-cell analysis in BRAF-mutant melanoma cells to identify compounds that block three distinct drug-tolerant epigenetic states associated with either one of the lysine-specific histone demethylases Kdm1a or Kdm4b, or BET proteins.
- Mehwish Khaliq
- , Mohan Manikkam
- & Mohammad Fallahi-Sichani
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Article
| Open AccessHigh-throughput phenotypic screen and transcriptional analysis identify new compounds and targets for macrophage reprogramming
Macrophages may polarize into different states with distinct regulatory functions for inflammation. Here the authors perform high-throughput in vitro screening of a library of ~4000 compounds to identify those with specific effects on human macrophage polarization, while RNAseq helps uncover the targets and pathways mediating these effects.
- Guangan Hu
- , Yang Su
- & Jianzhu Chen
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| Open Access3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels
Cellular models are needed to study disease in vitro and to screen drugs for toxicity and efficacy. Here the authors develop a bioprinting approach to transfer spheroids into self-healing support hydrogels at high resolution, which enables their patterning and fusion into high-cell density microtissues of prescribed spatial organization.
- Andrew C. Daly
- , Matthew D. Davidson
- & Jason A. Burdick
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Article
| Open AccessPlasmonic nanoparticle amyloid corona for screening Aβ oligomeric aggregate-degrading drugs
Effective screening of drugs to treat amyloid oligomeric aggregates associated with Alzheimer’s is needed for drug development. Here the authors report on the creation of an amyloid corona around a plasmonic nanoparticle to monitor amyloid degradation when exposed to potential drugs and demonstrate application.
- Dongtak Lee
- , Dongsung Park
- & Dae Sung Yoon
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Article
| Open AccessSteroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases
Sul-2 is a steroid sulfatase in c.elegans. Here the authors show that, in the absence of sul-2 enzymatic activity, worm lifespan is increased, and that chemical inhibition ameliorates symptoms of neurodegenerative disorders in worms and mice.
- Mercedes M. Pérez-Jiménez
- , José M. Monje-Moreno
- & Manuel J. Muñoz
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Article
| Open AccessComputationally predicting clinical drug combination efficacy with cancer cell line screens and independent drug action
Computational models that can predict drug combination efficacy are often based on drug synergy. Here, the authors develop a different approach to computationally predict the efficacy of drug combinations using monotherapy data from high-throughput cancer cell line screens.
- Alexander Ling
- & R. Stephanie Huang
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Article
| Open AccessPharmacological targeting of MCL-1 promotes mitophagy and improves disease pathologies in an Alzheimer’s disease mouse model
Previous work suggests that mitophagy in neurons is could be therapeutic in Alzheimer’s disease (AD). Here, the authors screen a library of drugs and identify UMI-77, a mitophagy inducer with beneficial effects in an AD mouse model, by binding MCL-1, which they identify as a mitophagy receptor.
- Xufeng Cen
- , Yanying Chen
- & Hongguang Xia
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Article
| Open AccessA combined high-throughput and high-content platform for unified on-chip synthesis, characterization and biological screening
On-chip synthesis and screening has been used to automate drug discovery but on-chip analysis still remains a major limitation. Here, the authors report on a dendrimer-based surface patterning method to create nanodroplet arrays on materials which allow for on-chip high-throughput analysis.
- Maximilian Benz
- , Arndt Asperger
- & Pavel A. Levkin
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Article
| Open AccessA nanoluciferase SARS-CoV-2 for rapid neutralization testing and screening of anti-infective drugs for COVID-19
A high-throughput platform would greatly facilitate coronavirus disease 2019 (COVID-19) serological testing and antiviral screening. To address this, Shi and colleagues present a high-throughput nanoluciferase severe respiratory syndrome coronavirus 2 (SARS-CoV2-Nluc), and show that it has potential for large-scale vaccine evaluation and neutralizing antibody testing.
- Xuping Xie
- , Antonio E. Muruato
- & Pei-Yong Shi
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| Open AccessBoth Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease
Coronavirus main protease is essential for viral polyprotein processing and maturation. Here Fu et al. report efficient inhibition of SARS-CoV-2 replication using two inhibitors - Boceprevir and GC376 - targeting the active site of the main viral protease.
- Lifeng Fu
- , Fei Ye
- & George Fu Gao
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Article
| Open AccessA scalable CRISPR/Cas9-based fluorescent reporter assay to study DNA double-strand break repair choice
Cells employ different repair pathways to repair DNA double strand breaks. Here, the authors develop a CRISPR/Cas9-dependent method to study choices in DNA repair called the Color Assay Tracing-Repair (CAT-R) which simultaneously measure outcomes of DSB repair via end-protection and end-resection pathways.
- Paris Roidos
- , Stephanie Sungalee
- & Balca R. Mardin
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| Open AccessIn vitro Cas9-assisted editing of modular polyketide synthase genes to produce desired natural product derivatives
Several different genetic strategies have been reported for the modification of polyketide synthases but the highly repetitive modular structure makes this difficult. Here the authors report on an adapted Cas9 reaction and Gibson assembly to edit a target region of the polyketide synthases gene in vitro.
- Kei Kudo
- , Takuya Hashimoto
- & Kazuo Shin-ya
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| Open AccessStructure-based evolution of a promiscuous inhibitor to a selective stabilizer of protein–protein interactions
Small molecule stabilizers of protein–protein interactions hold great therapeutic potential. Based on virtual screening and molecular docking, the authors here develop a strategy to evolve weak, promiscuous inhibitors of 14-3-3 interactions into selective stabilizers of the 14-3-3/ChREBP complex.
- Eline Sijbesma
- , Emira Visser
- & Christian Ottmann
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Article
| Open AccessA cancer drug atlas enables synergistic targeting of independent drug vulnerabilities
Drug synergies impact the efficacy of combination therapies but are difficult to identify. Here Narayan et al. describe the drug atlas, a method to predict effective drug combinations from common exclusive drug effects providing a resource for exploring and understanding effective drug combinations.
- Ravi S. Narayan
- , Piet Molenaar
- & Bart A. Westerman
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Article
| Open AccessTargeting codon 158 p53-mutant cancers via the induction of p53 acetylation
Codon 158 gain-of-function mutant p53 (158-mutp53) promotes tumourigenesis in lung cancer. Here, the authors show that 158-mutp53 render cancers sensitive to cisplatin and p53 acetylation agents through a mechanism where acetylated mutant p53 upregulates TRAIP and inhibits NF-ĸB signaling.
- Li Ren Kong
- , Richard Weijie Ong
- & Boon Cher Goh
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Article
| Open AccessIdentification of therapeutics that target eEF1A2 and upregulate utrophin A translation in dystrophic muscles
One potential approach for the treatment of Duchenne muscular dysrophy is to increase expression of the dystrophin homolog utrophin. Here, the authors show that eEF1A2 regulates utrophin expression, and show that 2 FDA-approved drugs upregulate eEIF1A2 and utrophin level in mice, leading to improvement of the dystrophic phenotype.
- Christine Péladeau
- , Nadine Adam
- & Bernard J. Jasmin
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Article
| Open Access2,6-Diaminopurine as a highly potent corrector of UGA nonsense mutations
Nonsense mutations can be corrected by several molecules that activate readthrough of premature termination codon. Here, the authors report that 2,6-diaminopurine efficiently corrects UGA nonsense mutations with no significant toxicity.
- Carole Trzaska
- , Séverine Amand
- & Fabrice Lejeune
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Article
| Open AccessAmino acid levels determine metabolism and CYP450 function of hepatocytes and hepatoma cell lines
Hepatocytes grown in a dish are immature and do not metabolize compounds as a real liver would. Here, the authors supply stem cell-derived hepatocytes with amino acids at a higher concentration than nutritionally necessary, changing the metabolism of these cells, making them more mature and useful for drug screening and toxicity studies.
- Ruben Boon
- , Manoj Kumar
- & Catherine M. Verfaillie
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Article
| Open AccessExploiting loss of heterozygosity for allele-selective colorectal cancer chemotherapy
Allelic losses occurring in cancer cells have been suggested as potential targets for therapy. Here, the authors show how recurring loss of heterozygosity of a drug metabolic gene in colorectal cancers can be exploited using a low molecular weight compound.
- Veronica Rendo
- , Ivaylo Stoimenov
- & Tobias Sjöblom
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Article
| Open AccessTargeting FROUNT with disulfiram suppresses macrophage accumulation and its tumor-promoting properties
The cytoplasmic protein FROUNT can bind to chemokine receptors and enhance chemokine signalling. Here, the authors show that inhibiting FROUNT in macrophages either by knockdown of the gene or using the anti-alcoholism drug disulfiram, results in a reduction in tumour growth.
- Yuya Terashima
- , Etsuko Toda
- & Kouji Matsushima
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Article
| Open AccessTargeting the tumor vasculature with engineered cystine-knot miniproteins
Cystine-knot miniprotein are small, highly stable, disulfide-rich peptides with increasing potential as drugs and tumor imaging agents. Here the authors develop cystine-knot miniproteins targeting the vascular tumor marker EDB, and use them as probes for in vivo tumor vasculature imaging.
- Bonny Gaby Lui
- , Nadja Salomon
- & Ugur Sahin
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Article
| Open AccessCombining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness
Trypanosoma brucei relies on uptake and conversion of purines from the host, which constitutes a potential drug target. Here, Hulpia et al. combine structural elements from known trypanocidal nucleoside analogues and develop a potent trypanocide with curative activity in animal models of acute and late stage sleeping sickness.
- Fabian Hulpia
- , Dorien Mabille
- & Serge Van Calenbergh
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Article
| Open AccessA high-throughput screen identifies that CDK7 activates glucose consumption in lung cancer cells
Many cancer cells have increased glucose consumption compared to normal cells, a feature that can be exploited therapeutically. Here, the authors carry out a chemical screen and identify compounds that selectively blocks glucose metabolism in non-small-cell lung cancer cell lines.
- Chiara Ghezzi
- , Alicia Wong
- & Peter M. Clark
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Article
| Open AccessAn in vitro model maintaining taxon-specific functional activities of the gut microbiome
The authors present an in vitro gut microbiome model that maintains the functional and compositional profiles of individual gut microbiomes, as assessed by metaproteomics. Gut microbiome responses to metformin in this model correlate with those shown in mice fed a high-fat diet.
- Leyuan Li
- , Elias Abou-Samra
- & Daniel Figeys
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Article
| Open AccessZebrafish behavioural profiling identifies GABA and serotonin receptor ligands related to sedation and paradoxical excitation
Some anesthetics despite being generally associated with sedation, can also increase brain activity—a phenomenon called paradoxical excitation. The authors identified dozens of compounds that generally decrease neuronal activity, but increase activity in the caudal hindbrain of zebrafish.
- Matthew N. McCarroll
- , Leo Gendelev
- & David Kokel
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Article
| Open AccessExploring use of unsupervised clustering to associate signaling profiles of GPCR ligands to clinical response
Identifying ligands which activate the specific effectors driving particular in vivo drug effects remains challenging. Here, the authors apply unsupervised clustering of pharmacodynamic parameters to classify GPCR ligands into different categories with similar signaling profiles and shared frequency of report of side effects.
- Besma Benredjem
- , Jonathan Gallion
- & Graciela Pineyro
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Article
| Open AccessRobust continuous in vitro culture of the Plasmodium cynomolgi erythrocytic stages
Present understanding of Plasmodium vivax biology is hampered by its inability to grow in vitro. Here, the authors developed an in vitro culture of its simian counterpart, P. cynomolgi, which shares morphological and phenotypic similarities with P. vivax, initiating a new phase in vivax research.
- Adeline C. Y. Chua
- , Jessica Jie Ying Ong
- & Pablo Bifani
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Article
| Open AccessMarrying chemistry with biology by combining on-chip solution-based combinatorial synthesis and cellular screening
High-throughput cell-based screening of compound libraries is utilised in drug development; however, a lack of compatible methods limits direct synthesis and testing. Here, the authors present a diverse chip based synthesis system which can be combined with cell screening and demonstrate the application.
- Maximilian Benz
- , Mijanur R. Molla
- & Pavel A. Levkin
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Article
| Open AccessIdentification of a potent benzoxaborole drug candidate for treating cryptosporidiosis
Cryptosporidium infection can cause severe diarrhea with limited treatment options available. Here, Lunde et al. perform a drug repositioning screen with a library of benzoxaboroles and identify AN7973 as potent inhibitor of intracellular parasite development with good efficacy in murine and neonatal dairy calf disease models.
- Christopher S. Lunde
- , Erin E. Stebbins
- & Christopher D. Huston