Featured
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| Open AccessZSP1601, 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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Perspective
| Open AccessThe 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 AccessTime-of-day defines NAD+ efficacy to treat diet-induced metabolic disease by synchronizing the hepatic clock in mice
The timing of NAD + supply determines its efficacy to treat metabolic disease. Here, the authors show that increasing NAD + at the early active phase maximizes weight loss and glucose regulation in mice. NAD + can displace the phase of the liver clock which can cause circadian misalignment.
- Quetzalcoatl Escalante-Covarrubias
- , Lucía Mendoza-Viveros
- & Lorena Aguilar-Arnal
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Article
| Open AccessOn-demand male contraception via acute inhibition of soluble adenylyl cyclase
Half of all pregnancies are unintended; thus, existing family planning options are inadequate. This proof-of-concept study validates an on-demand contraception strategy for men, showing high effectiveness in quickly and temporarily reducing male fertility in mice.
- Melanie Balbach
- , Thomas Rossetti
- & Lonny R. Levin
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Article
| Open AccessPreclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation
The search for antivirals against SARS-CoV-2 continue due to the emergence of variants of concerns, able to escape the vaccinal humoral response. In this work, authors pre-clinically explore the potential of kinetin against SARS-CoV-2, which could be used alone or in combination with other antivirals.
- Thiago Moreno L. Souza
- , Vagner D. Pinho
- & Jaime A. Rabi
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Article
| Open AccessThe dopamine transporter antiports potassium to increase the uptake of dopamine
The dopamine transporter, DAT, controls dopamine signaling by facilitating its reuptake using the Na+ gradient as driving force. Here, the authors uncover that an antiport of K+ ions also contributes to setting the rate of DAT-mediated dopamine clearance.
- Solveig G. Schmidt
- , Mette Galsgaard Malle
- & Claus J. Loland
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Article
| Open AccessIndisulam targets RNA splicing and metabolism to serve as a therapeutic strategy for high-risk neuroblastoma
The prognosis of high-risk neuroblastoma is poor despite the availability of multimodal treatment. Here the authors show that high-risk neuroblastoma is sensitive to indisulam, a selective degrader of the splicing factor RBM39 through the dual targeting of RNA splicing and metabolism.
- Anke Nijhuis
- , Arti Sikka
- & Hector C. Keun
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Article
| Open AccessAn orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion
Huntington’s disease (HD) results from the abnormal expansion of CAG repeats in exon 1 of the HTT gene. Here, the authors show that orally available, brain penetrant molecule branaplam lowers HTT transcript by promoting inclusion of a poison exon or pseudoexon.
- Caroline Gubser Keller
- , Youngah Shin
- & Rajeev Sivasankaran
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Article
| Open AccessPreclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19
The 3CL protease of SARS-CoV-2 is inhibited by PF-00835231 in vitro. Here, the authors show that the prodrug PF-07304814 has broad spectrum activity, inhibiting SARS-CoV and SARS-CoV-2 in mice and its ADME and safety profile support clinical development.
- Britton Boras
- , Rhys M. Jones
- & Charlotte Allerton
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Article
| Open AccessThe antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter
Vilazodone (VLZ) is a drug for the treatment of major depressive disorders that targets the serotonin transporter (SERT). Here, the authors combine pharmacology measurements and cryo-EM structural analysis to characterize VLZ binding to SERT and observe that VLZ exhibits non-competitive inhibition of serotonin transport and binds with nanomolar affinity to an allosteric site in SERT.
- Per Plenge
- , Dongxue Yang
- & Claus J. Loland
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Article
| Open AccessTranslational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis
The αvβ6 integrin is key in activating the pro-fibrotic cytokine TGFβ in idiopathic pulmonary fibrosis. Here, the authors show an inhaled small molecule αvβ6 inhibitor GSK3008348 induces prolonged inhibition of TGFβ signaling pathways in human and murine models of lung fibrosis via αvβ6 degradation.
- Alison E. John
- , Rebecca H. Graves
- & Robert J. Slack
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Article
| Open AccessDietary serine-microbiota interaction enhances chemotherapeutic toxicity without altering drug conversion
The gut microbiota can alter the effects of anticancer fluoropyrimidines such as 5-fluorodeoxyuridine (FUdR) in the model organism C. elegans. Here, the authors show that these effects are further affected by diet, and dietary thymidine and serine increase FUdR toxicity in C. elegans via different mechanisms.
- Wenfan Ke
- , James A. Saba
- & Eyleen J. O’Rourke
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Article
| Open AccessAntimalarial activity of primaquine operates via a two-step biochemical relay
Primaquine (PQ) is a widely used anti-malaria drug, but its mechanism of action is unclear. Here, Camarda et al. show that PQ’s activity against liver and sexual Plasmodium stages depends on generation of hydroxylated-PQ metabolites (OH-PQm), which, undergoing further reactions, results in production of H2O2.
- Grazia Camarda
- , Piyaporn Jirawatcharadech
- & Giancarlo A. Biagini
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Article
| Open AccessSystemic neurotransmitter responses to clinically approved and experimental neuropsychiatric drugs
The precise relationship between neurobehavioural effects and neurotransmitter effects of psychiatric drugs are not always understood. Here the authors develop a database documenting the neurotransmitter response in rats to 258 different neuropsychiatric drugs, and conclude that this neurotransmitter response does not, in general, reflect the current categorisation of those drugs.
- Hamid R. Noori
- , Lewis H. Mervin
- & Rainer Spanagel
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Article
| Open AccessA small molecule inhibitor of Rheb selectively targets mTORC1 signaling
Aberrant mTORC1 signaling is linked to several chronic diseases. Here, the authors develop a small molecule inhibitor that binds the small G-protein Rheb and selectively blocks mTORC1 signaling, holding potential for therapeutic applications.
- Sarah J. Mahoney
- , Sridhar Narayan
- & Eddine Saiah
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Article
| Open AccessCreation of a long-acting nanoformulated dolutegravir
Current ART for treatment of HIV-1 infection requires a strict daily regimen adherence. Herein, the authors report the manufacture and characterization of a nanoformulated dolutegravir prodrug with improved cell and tissue penetration, a remarkable apparent half-life and the potential for bimonthly drug administration.
- Brady Sillman
- , Aditya N. Bade
- & Howard E. Gendelman
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Article
| Open AccessHydralazine induces stress resistance and extends C. elegans lifespan by activating the NRF2/SKN-1 signalling pathway
Hydralazine is an FDA approved drug for the treatment of hypertension. Here, Dehghan et al. report that hydralazine triggers the cellular oxidative stress response by activating NRF2/SKN-1 signaling and extends C. elegans healthy lifespan, suggesting hydralazine may have potential to treat age-associated diseases more broadly.
- Esmaeil Dehghan
- , Yiqiang Zhang
- & Hamid Mirzaei
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Article
| Open AccessMolecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors
The heterogeneity of colorectal cancer has important clinical and therapeutic implications. Here the authors analysed the responses of a large biobank of organoids and xenografts derived from colorectal patients to a panel of clinically relevant therapeutic agents to identify genes signatures associated with drug response.
- Moritz Schütte
- , Thomas Risch
- & Marie-Laure Yaspo
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Article
| Open AccessThe antifungal caspofungin increases fluoroquinolone activity against Staphylococcus aureus biofilms by inhibiting N-acetylglucosamine transferase
Biofilms formed byStaphylococcus aureus are poorly responsive to antibiotics. Here, Siala et al. show that an antifungal drug (caspofungin) enhances the activity of fluoroquinolone antibiotics against S. aureus biofilms by inhibiting an enzyme involved in synthesis of the biofilm matrix.
- Wafi Siala
- , Soňa Kucharíková
- & Françoise Van Bambeke
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Article
| Open AccessStereochemical bias introduced during RNA synthesis modulates the activity of phosphorothioate siRNAs
Therapeutic oligonucleotides can be made more stable by substituting their achiral phosphodiester groups for chiral phosphorothioate linkages. Here, the authors present a synthesis of phosphorothioated RNAs, where the activator controls strand stereochemistry, and also the activity of assembled siRNAs.
- Hartmut Jahns
- , Martina Roos
- & Jonathan Hall
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Quantitative high throughput screening using a primary human three-dimensional organotypic culture predicts in vivo efficacy
Tumour microenvironment affects the outcome of pharmacological anticancer treatments. Here, Kenny et al. show that organotypic cultures of ovarian cancer cells can recapitulate metastasis. They identify several new compounds that block cancer invasion and metastasis and improve survival in mouse models.
- Hilary A. Kenny
- , Madhu Lal-Nag
- & Ernst Lengyel
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Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease
Selective targeting of cancer cells may improve therapeutic efficacy while reducing adverse effects. Here, Ueki et al.report selective activation of an anticancer drug upon removal of an acetylated lysine group by histone deacetylases and the tumour-associated protease cathepsin L.
- Nobuhide Ueki
- , Siyeon Lee
- & Michael J. Hayman
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Article
| Open AccessDrug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin
Anthracycline-based drugs can kill cancer cells by inhibiting topoisomerase II and promoting DNA double-strand breaks. Pang et al. show that anthracyclines also induce eviction of histones from open chromatin regions and, in doing so, modulate DNA repair and apoptosis in human cancer cells.
- Baoxu Pang
- , Xiaohang Qiao
- & Jacques Neefjes
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Single-cell and subcellular pharmacokinetic imaging allows insight into drug action in vivo
Current pharmacokinetic models describe the distribution of drugs within tissues but usually lack single-cell resolution. Here Weissleder and colleagues visualize the subcellular distribution of an anticancer drug in real time in living animals and develop a model to extrapolate these findings to humans.
- Greg M. Thurber
- , Katy S. Yang
- & Ralph Weissleder
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A safe lithium mimetic for bipolar disorder
Lithium is commonly used to treat bipolar disorder, but it exerts side effects at doses close to the therapeutic range. Singh and colleagues screen a collection of clinical compounds and find that ebselen induces lithium-like effects on mouse models of bipolar disorder by inhibiting inositol monophosphatase.
- Nisha Singh
- , Amy C. Halliday
- & Grant C. Churchill
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Article |
Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC
Metformin is used to treat diabetes and its use has been associated with reduced cancer incidence, but the mechanism is unclear. In this study, metformin is shown to alter microRNA expression including an increase in mir-33a, which decreases the expression of the oncogenec-Myc.
- Giovanni Blandino
- , Mariacristina Valerio
- & Sabrina Strano