Explanipedia

Discovery of Potent Benzothiazole Inhibitors of Oxidoreductase NQO2, a Target for Inflammation and Cancer Open

Asma A. Belgath, Aya M. Emam, Joshua Taujanskas, Richard A. Bryce, Sally Freeman , et al. · 2024

Inhibitors of NQO2 (NRH: quinone oxidoreductase) have potential application in several areas of medicine and pharmacology, including cancer, neurodegeneration (PD and AD), stroke, and diabetes. Here, resveratrol, a known inhibitor of NQO2,…

Virtual screening-led design of inhibitor scaffolds for the NLRP3 inflammasome Open

Sherihan El‐Sayed, Emily McMahon, Sondos Musleh, Sally Freeman, David Brough , et al. · 2024

The NLRP3 inflammasome is a key target for drug discovery due to its implication in a range of inflammation-related diseases. In this work, we identify new inhibitors of the NLRP3 inflammasome via a hierarchical virtual screening strategy …

Brazilin is a natural product inhibitor of the NLRP3 inflammasome Open

Emily McMahon, Sherihan El‐Sayed, Jack Green, Christopher Hoyle, Lorna M. FitzPatrick , et al. · 2024

Excessive or aberrant NLRP3 inflammasome activation has been implicated in the progression and initiation of many inflammatory conditions; however, currently no NLRP3 inflammasome inhibitors have been approved for therapeutic use in the cl…

Squaramides enhance NLRP3 inflammasome activation by lowering intracellular potassium Open

Paula I. Seoane, James Beswick, Andrew G. Leach, Tessa Swanton, Lucy Morris , et al. · 2023

Brazilin is a Natural Product Inhibitor of the NLRP3 Inflammasome Open

Emily McMahon, Sherihan El‐Sayed, Jack Green, Christopher Hoyle, Lorna M. FitzPatrick , et al. · 2023

Excessive or aberrant NLRP3 inflammasome activation has been implicated in the progression and initiation of many inflammatory conditions; however, currently no NLRP3 inflammasome inhibitors have been approved for therapeutic use in the cl…

PB0376 Vacuolar-Type ATPase Dependent Acidification of Megakaryocyte and Platelet α-Granules Maintains Packaging of VWF Open

WHA Kahr, Chan Lü, Jing Wu, Fred G. Pluthero, Li Li , et al. · 2023

Background: Hydroxyurea (HU), α-Interferon (αIFN), anagrelide (ANA) and ruxolitinib (Ruxo) are used in Myeloproliferative Neoplasms (MPN) treatment, conditions associated to thrombosis.Aims: Considering that large platelets could be relate…

Evaluation of 4-Aminoquinoline Hydrazone Analogues as Potential Leads for Drug-Resistant Malaria Open

Rachael N. Magwaza, Muna Abubaker, Buthaina Hussain, Michael Haley, Kevin N. Couper , et al. · 2023

The emergence of resistance to first-line antimalarial drugs calls for the development of new therapies for drug-resistant malaria. The efficacy of quinoline-based antimalarial drugs has prompted the development of novel quinolines. A pane…

Computational Investigation of Mechanisms for pH Modulation of Human Chloride Channels Open

Kathleen Elverson, Sally Freeman, Forbes Manson, Jim Warwicker · 2023

Many transmembrane proteins are modulated by intracellular or extracellular pH. Investigation of pH dependence generally proceeds by mutagenesis of a wide set of amino acids, guided by properties such as amino-acid conservation and structu…

Evaluation of Novel 4 – Aminoquinoline Hydrazone Analogues as Potential Leads for Drug-Resistant Malaria Open

Rachael N. Magwaza, Muna Abubaker, Buthaina Hussain, Michael Haley, Kevin N. Couper , et al. · 2023

The emergence of resistance to first-line antimalarial drugs calls for development of new therapies for drug-resistant malaria. The efficacy of quinoline-based antimalarial drugs has prompted the development of novel quinolines. A panel of…

Discovery of an inhibitor of DNA-driven inflammation that preferentially targets the AIM2 inflammasome Open

Jack Green, Lina Y. El‐Sharkawy, S. Roth, Jie Zhu, Jiayu Cao , et al. · 2023

Inflammation driven by DNA sensors is now understood to be important to disease pathogenesis. Here, we describe new inhibitors of DNA sensing, primarily of the inflammasome forming sensor AIM2. Biochemistry and molecular modeling has revea…

Tadalafil Rescues the p.M325T Mutant of Best1 Chloride Channel Open

Kathleen Elverson, Jim Warwicker, Sally Freeman, Forbes Manson · 2023

Bestrophin 1 (Best1) is a chloride channel that localises to the plasma membrane of retinal pigment epithelium (RPE) cells. Mutations in the BEST1 gene are associated with a group of untreatable inherited retinal dystrophies (IRDs) called …

Computational investigation of mechanisms for pH modulation of human chloride channels Open

Kathleen Elverson, Sally Freeman, Forbes Manson, Jim Warwicker · 2022

Many transmembrane proteins are modulated by intracellular or extracellular pH. Investigation of pH-dependence generally proceeds by mutagenesis of a wide set of amino acids, guided by properties such as amino acid conservation and structu…

Probing the effect of NEK7 and cofactor interactions on dynamics of NLRP3 monomer using molecular simulation Open

Sherihan El‐Sayed, Sally Freeman, Richard A. Bryce · 2022

The NLRP3 inflammasome is a cytoplasmic complex that regulates the activation of inflammatory cytokines and, given its implication in a range of diseases, is an important therapeutic target. The cofactor ATP and the centrosomal kinase NEK7…

A Selective Review and Virtual Screening Analysis of Natural Product Inhibitors of the NLRP3 Inflammasome Open

Sherihan El‐Sayed, Sally Freeman, Richard A. Bryce · 2022

The NLRP3 inflammasome is currently an exciting target for drug discovery due to its role in various inflammatory diseases; however, to date, no NLRP3 inhibitors have reached the clinic. Several studies have used natural products as hit co…

Targeting firing rate neuronal homeostasis can prevent seizures Open

Fred Mulroe, Wei‐Hsiang Lin, Connie Mackenzie‐Gray Scott, Najat Aourz, Yuen Ngan Fan , et al. · 2022

Manipulating firing-rate neuronal homeostasis, which enables neurons to regulate their intrinsic excitability, offers an attractive opportunity to prevent seizures. However, to date, no drug-based interventions have been reported that mani…

Discovery of an AIM2 inflammasome inhibitor for the treatment of DNA-driven inflammatory disease Open

Jack Green, Lina Y. El‐Sharkawy, Stefan Roth, Jie Zhu, Jiayu Cao , et al. · 2022

Inflammation driven by DNA sensors is now understood to be central to disease pathogenesis. Here we describe new inhibitors of pathogenic DNA sensing, primarily of the inflammasome forming sensor AIM2. Molecular modelling and biochemistry …

SAR of Novel 3-Arylisoquinolinones:meta-Substitution on the Aryl Ring Dramatically Enhances Antiproliferative Activity through Binding to Microtubules Open

Mai A. Elhemely, Asma A. Belgath, Sherihan El‐Sayed, Kepa K. Burusco, Manikandan Kadirvel , et al. · 2022

A set of meta-substituted 3-arylisoquinolinones have been identified that show substantial cytotoxicity in breast, liver, lung and colon cancer cell lines; these are up to 700-fold more active than the corresponding para anal…

Targeting neuronal homeostasis to prevent seizures Open

Fred Mulroe, Wei‐Hsiang Lin, Connie Mackenzie-Gray Scott, Najat Aourz, Yuen Ngan Fan , et al. · 2022

Manipulating neuronal homeostasis, which enables neurons to regulate their intrinsic excitability, offers an attractive opportunity to prevent seizures. However, no anticonvulsant compounds have yet been reported that directly manipulate n…

A carvedilol analogue, VK‐II‐86, prevents hypokalaemia‐induced ventricular arrhythmia through novel multi‐channel effects Open

Victoria M. Robinson, Izzeddin Alsalahat, Sally Freeman, Charles Antzelevitch, Héctor Barajas-Martínez , et al. · 2021

Background and Purpose QT prolongation and intracellular Ca 2+ loading with diastolic Ca 2+ release via ryanodine receptors (RyR2) are the predominant mechanisms underlying hypokalaemia‐induced ventricular arrhythmia. We investigated the a…

Selected Derivatives of Erythromycin B-In Silico and Anti-Malarial Studies Open

Pranab K. Bhadra, Rachael N. Magwaza, Niroshini Nirmalan, Sally Freeman, Jill Barber , et al. · 2021

Erythromycin A is an established anti-bacterial agent against Gram-positive bacteria, but it is unstable to acid. This led to an evaluation of erythromycin B and its derivatives because these have improved acid stability. These compounds w…

BS10 A carvedilol analogue, VKII-86, prevents hypokalaemia-induced ventricular arrhythmia through novel multi-channel effects Open

Victoria M. Robinson, Izzeddin Alsalahat, Sally Freeman, Charles Antzelevitch, Héctor Barajas-Martínez , et al. · 2021

Background and Purpose Hypokalaemia is the most common electrolyte disturbance with a significant mortality due to the occurrence of ventricular arrhythmia. There is currently no available treatment to prevent ventricular arrhythmia in pat…

Inhibition of aggregation of amyloid-β through covalent modification with benzylpenicillin; potential relevance to Alzheimer's disease Open

Izzeddin Alsalahat, Zubida M. Al‐Majdoub, Mutasem O. Taha, Jill Barber, Harmesh Aojula , et al. · 2021

Inhibiting the NLRP3 Inflammasome Open

Lina Y. El‐Sharkawy, David Brough, Sally Freeman · 2020

Inflammasomes are protein complexes which are important in several inflammatory diseases. Inflammasomes form part of the innate immune system that triggers the activation of inflammatory cytokines interleukin (IL)-1β and IL-18. The inflamm…

LRRC8A is essential for hypotonicity-, but not for DAMP-induced NLRP3 inflammasome activation Open

Jack Green, Tessa Swanton, Lucy Morris, Lina Y. El‐Sharkawy, James Cook , et al. · 2020

The NLRP3 inflammasome is a multi-molecular protein complex that converts inactive cytokine precursors into active forms of IL-1β and IL-18. The NLRP3 inflammasome is frequently associated with the damaging inflammation of non-communicable…

Author response: LRRC8A is essential for hypotonicity-, but not for DAMP-induced NLRP3 inflammasome activation Open

Jack Green, Tessa Swanton, Lucy Morris, Lina Y. El‐Sharkawy, James Cook , et al. · 2020

Article Figures and data Abstract eLife digest Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Metrics Abstract The NLRP3 inflammasome is a m…

LRRC8A regulates hypotonicity-induced NLRP3 inflammasome activation Open

Jack Green, Tessa Swanton, Lucy Morris, Lina Y. El‐Sharkawy, James Cook , et al. · 2020

The NLRP3 inflammasome is a multi-molecular protein complex that converts inactive cytokine precursors into active forms of IL-1β and IL-18. The NLRP3 inflammasome is frequently associated with the damaging inflammation of non-communicable…

Small Molecules Restore Bestrophin 1 Expression and Function of Both Dominant and Recessive Bestrophinopathies in Patient-Derived Retinal Pigment Epithelium Open

Jingshu Liu, Rachel L. Taylor, Richard A. Baines, Lisa Swanton, Sally Freeman , et al. · 2020

The restoration of bestrophin 1 function in patient-derived RPE confirms the US Food and Drug Administration-approved drug 4PBA as a promising therapeutic treatment for bestrophinopathies.

Resveratrol-mediated cleavage of amyloid β1–42 peptide: potential relevance to Alzheimer's disease Open

Sarmad Al-Edresi, Izzeddin Alsalahat, Sally Freeman, Harmesh Aojula, Jeffrey Penny · 2020

Selective inhibition of the K+ efflux sensitive NLRP3 pathway by Cl− channel modulation Open

Tessa Swanton, James Beswick, Halah Hammadi, Lucy Morris, Daniel M. Williams , et al. · 2020

The NLRP3 inflammasome regulates production of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, and contributes to inflammation exacerbating disease.

Discovery of potent 4-aminoquinoline hydrazone inhibitors of NRH:quinoneoxidoreductase-2 (NQO2) Open

Buthaina Hussein, Balqis Ikhmais, Manikandan Kadirvel, Rachael N. Magwaza, Gavin Halbert , et al. · 2019

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