Search Results

You searched for all publications:

with publication states 'Published (Approved)'
with Tags 'Non-Communicable Diseases'

Search Again...

These results only include publications that have been reviewed and processed by Diamond Light Source. To also view papers that have not yet been processed click here.

You can use the folder icon under Actions to collate papers as required. You can then click on View Folder in the left-hand navigation to review and/or download your folder.

Exact matches
Related results

307 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3, 4, 5, 6, 7, 8 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography	Identification of unprecedented ATP-competitive choline kinase inhibitors Francesca Quartieri , Marcella Nesi , Nilla R. Avanzi , Daniela Borghi , Elena Casale , Emiliana Corti , Ulisse Cucchi , Daniele Donati , Marina Fasolini , Eduard R. Felder , Arturo Galvani , Maria L. Giorgini , Antonio Lomolino , Maria Menichincheri , Christian Orrenius , Claudia Perrera , Stefania Re Depaolini , Federico Riccardi-Sirtori , Enea Salsi , Antonella Isacchi , Paola Gnocchi Bioorganic & Medicinal Chemistry Letters 51 DOI: 10.1016/j.bmcl.2021.128310 Diamond Proposal Number(s): [26586] Show Abstract ▼ Abstract: In this article we describe the identification of unprecedented ATP-competitive ChoKα inhibitors starting from initial hit NMS-P830 that binds to ChoKα in an ATP concentration-dependent manner. This result is confirmed by the co-crystal structure of NMS-P830 in complex with Δ75-ChoKα. NMS-P830 is able to inhibit ChoKα in cells resulting in the reduction of intracellular phosphocholine formation. A structure-based medicinal chemistry program resulted in the identification of selective compounds that have good biochemical activity, solubility and metabolic stability and are suitable for further optimization. The ChoKα inhibitors disclosed in this article demonstrate for the first time the possibility to inhibit ChoKα with ATP-competitive compounds.	Nov 2021
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Structure of the human marker of self 5-transmembrane receptor CD47 Gustavo Fenalti , Nicolas Villanueva , Mark Griffith , Barbra Pagarigan , Sirish Kaushik Lakkaraju , Richard Y.-C. Huang , Nadia Ladygina , Alok Sharma , David Mikolon , Mahan Abbasian , Jeffrey Johnson , Haralambos Hadjivassiliou , Dan Zhu , Philip P. Chamberlain , Ho Cho , Kandasamy Hariharan Nature Communications 12 DOI: 10.1038/s41467-021-25475-w Open Access Show Abstract ▼ Abstract: CD47 is the only 5-transmembrane (5-TM) spanning receptor of the immune system. Its extracellular domain (ECD) is a cell surface marker of self that binds SIRPα and inhibits macrophage phagocytosis, and cancer immuno-therapy approaches in clinical trials are focused on blocking CD47/SIRPα interaction. We present the crystal structure of full length CD47 bound to the function-blocking antibody B6H12. CD47 ECD is tethered to the TM domain via a six-residue peptide linker (114RVVSWF119) that forms an extended loop (SWF loop), with the fundamental role of inserting the side chains of W118 and F119 into the core of CD47 extracellular loop region (ECLR). Using hydrogen-deuterium exchange and molecular dynamics simulations we show that CD47’s ECLR architecture, comprised of two extracellular loops and the SWF loop, creates a molecular environment stabilizing the ECD for presentation on the cell surface. These findings provide insights into CD47 immune recognition, signaling and therapeutic intervention.	Sep 2021
B21-High Throughput SAXS	Autosomal recessive cutis Laxa 1C mutations disrupt the structure and interactions of latent TGFβ binding protein-4 Yasmene F. Alanazi , Michael P. Lockhart-Cairns , Stuart A. Cain , Thomas A. Jowitt , Anthony S. Weiss , Clair Baldock Frontiers In Genetics 12 DOI: 10.3389/fgene.2021.706662 Diamond Proposal Number(s): [1580] Open Access Show Abstract ▼ Abstract: Latent TGFβ binding protein-4 (LTBP4) is a multi-domain glycoprotein, essential for regulating the extracellular bioavailability of TGFβ and assembly of elastic fibre proteins, fibrillin-1 and tropoelastin. LTBP4 mutations are linked to autosomal recessive cutis laxa type 1C (ARCL1C), a rare congenital disease characterised by high mortality and severely disrupted connective tissues. Despite the importance of LTBP4, the structure and molecular consequences of disease mutations are unknown. Therefore, we analysed the structural and functional consequences of three ARCL1C causing point mutations which effect highly conserved cysteine residues. Our structural and biophysical data show that the LTBP4 N- and C-terminal regions are monomeric in solution and adopt extended conformations with the mutations resulting in subtle changes to their conformation. Similar to LTBP1, the N-terminal region is relatively inflexible, whereas the C-terminal region is flexible. Interaction studies show that one C-terminal mutation slightly decreases binding to fibrillin-1. We also found that the LTBP4 C-terminal region directly interacts with tropoelastin which is perturbed by both C-terminal ARCL1C mutations, whereas an N-terminal mutation increased binding to fibulin-4 but did not affect the interaction with heparan sulphate. Our results suggest that LTBP4 mutations contribute to ARCL1C by disrupting the structure and interactions of LTBP4 which are essential for elastogenesis in a range of mammalian connective tissues.	Sep 2021
B16-Test Beamline	Multi-scale structural and mechanical characterisation in bioinspired polyurethane-based pancreatic cancer model Jingyi Mo , Nathanael Leung , Priyanka Gupta , Bin Zhu , Hui Xing , Jiao Zhang , Eirini Velliou , Tan Sui Journal Of Materials Research And Technology 68 DOI: 10.1016/j.jmrt.2021.09.041 Diamond Proposal Number(s): [20046] Open Access Show Abstract ▼ Abstract: In this work, novel bioinspired polyurethane (PU) scaffolds were fabricated via freeze casting for PU-based Pancreatic Ductal Adenocarcinoma (PDAC) model. In order to reproduce the tumour micro-environment that facilitates cellular kinetics, the PU scaffolds were surface modified with extracellular matrix (ECM) proteins including collagen and fibronectin (Col and FN). Synchrotron-based small- and wide-angle X-ray scattering (SAXS/WAXS) techniques were applied to probe structural evolution during in situ mechanical testing. Strains at macroscopic, nano-, and lattice scales were obtained to investigate the effects of ECM proteins and pancreatic cell activities to PU scaffolds. Significant mechanical strengthening across length scales of PU scaffolds was observed in specimens surface modified by FN. A model of stiffness modulation via enhanced interlamellar recruitment is proposed to explain the multi-scale strengthening mechanisms. Understanding multi-scale deformation mechanisms of a series of PU scaffolds opens an opportunity in developing a novel pancreatic cancer model for studying cancer evolution and predicting outcomes of drug/treatments.	Sep 2021
I24-Microfocus Macromolecular Crystallography	Cooperative stabilisation of 14-3-3σ protein–protein interactions via covalent protein modification Marta Falcicchio , Jake A. Ward , Sara Y. Chothia , Jaswir Basran , Alisha Mohindra , Salvador Macip , Pietro Roversi , Richard G. Doveston Chemical Science 61 DOI: 10.1039/D1SC02120F Open Access Show Abstract ▼ Abstract: 14-3-3 proteins are an important family of hub proteins that play important roles in many cellular processes via a large network of interactions with partner proteins. Many of these protein–protein interactions (PPI) are implicated in human diseases such as cancer and neurodegeneration. The stabilisation of selected 14-3-3 PPIs using drug-like ‘molecular glues’ is a novel therapeutic strategy with high potential. However, the examples reported to date have a number of drawbacks in terms of selectivity and potency. Here, we report that WR-1065, the active species of the approved drug amifostine, covalently modifies 14-3-3σ at an isoform-unique cysteine residue, Cys38. This modification leads to isoform-specific stabilisation of two 14-3-3σ PPIs in a manner that is cooperative with a well characterised molecular glue, fusicoccin A. Our findings reveal a novel stabilisation mechanism for 14-3-3σ, an isoform with particular involvement in cancer pathways. This mechanism can be exploited to harness the enhanced potency conveyed by covalent drug molecules and dual ligand cooperativity. This is demonstrated in two cancer cell lines whereby the cooperative behaviour of fusicoccin A and WR-1065 leads to enhanced efficacy for inducing cell death and attenuating cell growth.	Sep 2021
B21-High Throughput SAXS	Regulation of human mTOR complexes by DEPTOR Matthias Wälchli , Karolin Berneiser , Francesca Mangia , Stefan Imseng , Louise-Marie Craigie , Edward Stuttfeld , Michael N. Hall , Timm Maier Elife 10 DOI: 10.7554/eLife.70871 Open Access Show Abstract ▼ Abstract: The vertebrate-specific DEP domain-containing mTOR interacting protein (DEPTOR), an oncoprotein or tumor suppressor, has important roles in metabolism, immunity, and cancer. It is the only protein that binds and regulates both complexes of mammalian target of rapamycin (mTOR), a central regulator of cell growth. Biochemical analysis and cryo-EM reconstructions of DEPTOR bound to human mTOR complex 1 (mTORC1) and mTORC2 reveal that both structured regions of DEPTOR, the PDZ domain and the DEP domain tandem (DEPt), are involved in mTOR interaction. The PDZ domain binds tightly with mildly activating effect, but then acts as an anchor for DEPt association that allosterically suppresses mTOR activation. The binding interfaces of the PDZ domain and DEPt also support further regulation by other signaling pathways. A separate, substrate-like mode of interaction for DEPTOR phosphorylation by mTOR complexes rationalizes inhibition of non-stimulated mTOR activity at higher DEPTOR concentrations. The multifaceted interplay between DEPTOR and mTOR provides a basis for understanding the divergent roles of DEPTOR in physiology and opens new routes for targeting the mTOR-DEPTOR interaction in disease.	Sep 2021
B21-High Throughput SAXS	Lipid cubic systems for sustained and controlled delivery of antihistamine drugs Michele Dully , Miriama Ceresnakova , David Murray , Tewfik Soulimane , Sarah P. Hudson Molecular Pharmaceutics 3 DOI: 10.1021/acs.molpharmaceut.1c00279 Open Access Show Abstract ▼ Abstract: Antihistamines are capable of blocking mediator responses in allergic reactions including allergic rhinitis and dermatological reactions. By incorporating various H1 receptor antagonists into a lipid cubic phase network, these active ingredients can be delivered locally over an extended period of time owing to the mucoadhesive nature of the system. Local delivery can avoid inducing unwanted side effects, often observed after systematic delivery. Lipid-based antihistamine delivery systems are shown here to exhibit prolonged release capabilities. In vitro drug dissolution studies investigated the extent and release rate of two model first-generation and two model second-generation H1 antagonist antihistamine drugs from two monoacyglycerol-derived lipid models. To optimize the formulation approach, the systems were characterized macroscopically and microscopically by small-angle X-ray scattering and polarized light to ascertain the mesophase accessed upon an incorporation of antihistamines of varying solubilities and size. The impact of encapsulating the antihistamine molecules on the degree of mucoadhesivity of the lipid cubic systems was investigated using multiparametric surface plasmon resonance. With the ultimate goal of developing therapies for the treatment of allergic reactions, the ability of the formulations to inhibit mediator release utilizing RBL-2H3 mast cells with the propensity to release histamine upon induction was explored, demonstrating no interference from the lipid excipient on the effectiveness of the antihistamine molecules.	Sep 2021
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}- N -methylpyridine-2-carboxamide (AZD5305): A PARP1–DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs Jeffrey W. Johannes , Amber Balazs , Derek Barratt , Michal Bista , Matthew D. Chuba , Sabina Cosulich , Susan E. Critchlow , Sébastien L. Degorce , Paolo Di Fruscia , Scott D. Edmondson , Kevin Embrey , Stephen Fawell , Avipsa Ghosh , Sonja J. Gill , Anders Gunnarsson , Sudhir M. Hande , Tom D. Heightman , Paul Hemsley , Giuditta Illuzzi , Jordan Lane , Carrie Larner , Elisabetta Leo , Lina Liu , Andrew Madin , Scott Martin , Lisa Mcwilliams , Mark J. O'Connor , Jonathan P. Orme , Fiona Pachl , Martin J. Packer , Xiaohui Pei , Andrew Pike , Marianne Schimpl , Hongyao She , Anna D. Staniszewska , Verity Talbot , Elizabeth Underwood , Jeffrey G. Varnes , Lin Xue , Tieguang Yao , Ke Zhang , Andrew X. Zhang , Xiaolan Zheng Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c01012 Diamond Proposal Number(s): [14631, 17180, 20015] Show Abstract ▼ Abstract: Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1–DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1–DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.	Sep 2021
I03-Macromolecular Crystallography	Optimization of an imidazo[1,2-a]pyridine series to afford highly selective type i1/2 dual Mer/Axl kinase inhibitors with in vivo efficacy William Mccoull , Scott Boyd , Martin R. Brown , Muireann Coen , Olga Collingwood , Nichola L. Davies , Ann Doherty , Gary Fairley , Kristin Goldberg , Elizabeth Hardaker , Guang He , Edward J. Hennessy , Philip Hopcroft , George Hodgson , Anne Jackson , Xiefeng Jiang , Ankur Karmokar , Anne-Laure Lainé , Nicola Lindsay , Yumeng Mao , Roshini Markandu , Lindsay Mcmurray , Neville Mclean , Lorraine Mooney , Helen Musgrove , J. Willem M. Nissink , Alexander Pflug , Venkatesh Pilla Reddy , Philip B. Rawlins , Emma Rivers , Marianne Schimpl , Graham F. Smith , Sharon Tentarelli , Jon Travers , Robert I. Troup , Josephine Walton , Cheng Wang , Stephen Wilkinson , Beth Williamson , Jon Winter-Holt , Dejian Yang , Yuting Zheng , Qianxiu Zhu , Paul D. Smith Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c00920 Diamond Proposal Number(s): [17180] Show Abstract ▼ Abstract: Inhibition of Mer and Axl kinases has been implicated as a potential way to improve the efficacy of current immuno-oncology therapeutics by restoring the innate immune response in the tumor microenvironment. Highly selective dual Mer/Axl kinase inhibitors are required to validate this hypothesis. Starting from hits from a DNA-encoded library screen, we optimized an imidazo[1,2-a]pyridine series using structure-based compound design to improve potency and reduce lipophilicity, resulting in a highly selective in vivo probe compound 32. We demonstrated dose-dependent in vivo efficacy and target engagement in Mer- and Axl-dependent efficacy models using two structurally differentiated and selective dual Mer/Axl inhibitors. Additionally, in vivo efficacy was observed in a preclinical MC38 immuno-oncology model in combination with anti-PD1 antibodies and ionizing radiation.	Sep 2021
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Design, synthesis and structural analysis of glucocerebrosidase imaging agents Gideon J. Davies , Rhianna J. Rowland , Yurong Chen , Imogen Breen , Liang Wu , Wendy A. Offen , Thomas Beenakker , Qin Su , Adrianus M. C. H. Van Den Nieuwendijk , Johannes M. F. G. Aerts , Marta Artola , Herman S. Overkleeft Chemistry – A European Journal DOI: 10.1002/chem.202102359 Diamond Proposal Number(s): [13587, 18598] Show Abstract ▼ Abstract: Gaucher disease (GD) is a lysosomal storage disorder caused by inherited deficiencies in β-glucocerebrosidase (GBA). Current treatments require rapid disease diagnosis and a means of monitoring therapeutic efficacy, both of which may be supported by the use of GBA-targeting activity-based probes (ABPs). Here, we report the synthesis and structural analysis of a range of cyclophellitol epoxide and aziridine inhibitors and ABPs for GBA. We demonstrate their covalent mechanism-based mode of action and uncover binding of the new N- functionalised aziridines to the ligand binding cleft. These inhibitors became scaffolds for the development of ABPs; the O6-fluorescent tags of which bind in an allosteric site at the dimer interface. Considering GBA’s preference for O6- and N -functionalised reagents, we synthesised a bi-functional aziridine ABP which we hoped would offer a more powerful imaging agent. Whilst this ABP binds to two unique active site clefts of GBA, no further benefit in potency was achieved over our first generation ABPs. Nevertheless, such ABPs should serve useful in the study of GBA in relation to GD and inform the design of future probes.	Sep 2021

Publications Database

Search Results

You searched for all publications:

Search Again...

Subject Areas (check all that apply) select all

Instruments used to collect data (check all that apply) select all

Collaborations involved (check all that apply) select all

Diamond Offline Facilities used

Relevant Technical Areas (check all that apply) select all

Menu for Anonymous User