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Instruments / Technical Area	Publication Details	Published
I08-Scanning X-ray Microscopy beamline (SXM)	Label-free in situ chemical characterization of amyloid plaques in human brain tissues James Everett , Jake Brooks , Vindy Tjendana Tjhin , Frederik Lermyte , Ian Hands-Portman , Germán Plascencia-Villa , George Perry , Peter J. Sadler , Peter B. O’connor , Joanna F. Collingwood , Neil D. Telling Acs Chemical Neuroscience DOI: 10.1021/acschemneuro.3c00756 Open Access Show Abstract ▼ Abstract: The accumulation of amyloid plaques and increased brain redox burdens are neuropathological hallmarks of Alzheimer’s disease. Altered metabolism of essential biometals is another feature of Alzheimer’s, with amyloid plaques representing sites of disturbed metal homeostasis. Despite these observations, metal-targeting disease treatments have not been therapeutically effective to date. A better understanding of amyloid plaque composition and the role of the metals associated with them is critical. To establish this knowledge, the ability to resolve chemical variations at nanometer length scales relevant to biology is essential. Here, we present a methodology for the label-free, nanoscale chemical characterization of amyloid plaques within human Alzheimer’s disease tissue using synchrotron X-ray spectromicroscopy. Our approach exploits a C–H carbon absorption feature, consistent with the presence of lipids, to visualize amyloid plaques selectively against the tissue background, allowing chemical analysis to be performed without the addition of amyloid dyes that alter the native sample chemistry. Using this approach, we show that amyloid plaques contain elevated levels of calcium, carbonates, and iron compared to the surrounding brain tissue. Chemical analysis of iron within plaques revealed the presence of chemically reduced, low-oxidation-state phases, including ferromagnetic metallic iron. The zero-oxidation state of ferromagnetic iron determines its high chemical reactivity and so may contribute to the redox burden in the Alzheimer’s brain and thus drive neurodegeneration. Ferromagnetic metallic iron has no established physiological function in the brain and may represent a target for therapies designed to lower redox burdens in Alzheimer’s disease. Additionally, ferromagnetic metallic iron has magnetic properties that are distinct from the iron oxide forms predominant in tissue, which might be exploitable for the in vivo detection of amyloid pathologies using magnetically sensitive imaging. We anticipate that this label-free X-ray imaging approach will provide further insights into the chemical composition of amyloid plaques, facilitating better understanding of how plaques influence the course of Alzheimer’s disease.	Mar 2024
I04-Macromolecular Crystallography	Discovery of a potent and selective CDKL5/GSK3 chemical probe that is neuroprotective Han Wee Ong , Yi Liang , William Richardson , Emily R. Lowry , Carrow I. Wells , Xiangrong Chen , Margaux Silvestre , Kelvin Dempster , Josie A. Silvaroli , Jeffery L. Smith , Hynek Wichterle , Navjot S. Pabla , Sila K. Ultanir , Alex N. Bullock , David H. Drewry , Alison D. Axtman Acs Chemical Neuroscience DOI: 10.1021/acschemneuro.3c00135 Diamond Proposal Number(s): [28172] Open Access Show Abstract ▼ Abstract: Despite mediating several essential processes in the brain, including during development, cyclin-dependent kinase-like 5 (CDKL5) remains a poorly characterized human protein kinase. Accordingly, its substrates, functions, and regulatory mechanisms have not been fully described. We realized that availability of a potent and selective small molecule probe targeting CDKL5 could enable illumination of its roles in normal development as well as in diseases where it has become aberrant due to mutation. We prepared analogs of AT-7519, a compound that has advanced to phase II clinical trials and is a known inhibitor of several cyclin-dependent kinases (CDKs) and cyclin-dependent kinase-like kinases (CDKLs). We identified analog 2 as a highly potent and cell-active chemical probe for CDKL5/GSK3 (glycogen synthase kinase 3). Evaluation of its kinome-wide selectivity confirmed that analog 2 demonstrates excellent selectivity and only retains GSK3α/β affinity. We next demonstrated the inhibition of downstream CDKL5 and GSK3α/β signaling and solved a co-crystal structure of analog 2 bound to human CDKL5. A structurally similar analog (4) proved to lack CDKL5 affinity and maintain potent and selective inhibition of GSK3α/β, making it a suitable negative control. Finally, we used our chemical probe pair (2 and 4) to demonstrate that inhibition of CDKL5 and/or GSK3α/β promotes the survival of human motor neurons exposed to endoplasmic reticulum stress. We have demonstrated a neuroprotective phenotype elicited by our chemical probe pair and exemplified the utility of our compounds to characterize the role of CDKL5/GSK3 in neurons and beyond.	Apr 2023
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Structural analysis and development of notum fragment screening hits Yuguang Zhao , William Mahy , Nicky J. Willis , Hannah L. Woodward , David Steadman , Elliott D. Bayle , Benjamin N. Atkinson , James Sipthorp , Luca Vecchia , Reinis R. Ruza , Karl Harlos , Fiona Jeganathan , Stefan Constantinou , Artur Costa , Svend Kjær , Magda Bictash , Patricia C. Salinas , Paul Whiting , Jean-Paul Vincent , Paul V. Fish , E. Yvonne Jones Acs Chemical Neuroscience DOI: 10.1021/acschemneuro.2c00325 Diamond Proposal Number(s): [16814] Open Access Show Abstract ▼ Abstract: The Wnt signaling suppressor Notum is a promising target for osteoporosis, Alzheimer’s disease, and colorectal cancers. To develop novel Notum inhibitors, we used an X-ray crystallographic fragment screen with the Diamond-SGC Poised Library (DSPL) and identified 59 fragment hits from the analysis of 768 data sets. Fifty-eight of the hits were found bound at the enzyme catalytic pocket with potencies ranging from 0.5 to >1000 μM. Analysis of the fragments’ diverse binding modes, enzymatic inhibitory activities, and chemical properties led to the selection of six hits for optimization, and five of these resulted in improved Notum inhibitory potencies. One hit, 1-phenyl-1,2,3-triazole 7, and its related cluster members, have shown promising lead-like properties. These became the focus of our fragment development activities, resulting in compound 7d with IC50 0.0067 μM. The large number of Notum fragment structures and their initial optimization provided an important basis for further Notum inhibitor development.	Jun 2022
I24-Microfocus Macromolecular Crystallography	Novel macrocyclic antagonists of the calcitonin gene-related peptide receptor: design, realization, and structural characterization of protein–ligand complexes Andrew D. Cansfield , Mark A. Ator , Joydeep Banerjee , Michael Bestwick , Andrea Bortolato , Giles A. Brown , Jason Brown , Kristina Butkovic , Julie E. Cansfield , John A. Christopher , Miles Congreve , Gabriella Cseke , Francesca Deflorian , Benjamin Dugan , Martina Petrovic Hunjadi , Antun Hutinec , Trinadh Kumar Inturi , Goran Landek , Jonathan Mason , Alistair O’brien , Gregory R. Ott , Renata Rupcic , Gordon Saxty , Stacey M. Southall , Rahela Zadravec , Stephen P. Watson Acs Chemical Neuroscience 96 DOI: 10.1021/acschemneuro.1c00696 Show Abstract ▼ Abstract: A series of macrocyclic calcitonin gene-related peptide (CGRP) receptor antagonists identified using structure-based design principles, exemplified by HTL0028016 (1) and HTL0028125 (2), is described. Structural characterization by X-ray crystallography of the interaction of two of the macrocycle antagonists with the CGRP receptor ectodomain is described, along with structure–activity relationships associated with point changes to the macrocyclic antagonists. The identification of non-peptidic/natural product-derived, macrocyclic ligands for a G protein coupled receptor (GPCR) is noteworthy.	Mar 2022
B23-Circular Dichroism	Circular dichroism spectroscopy identifies the β-adrenoceptor agonist salbutamol as a direct inhibitor of tau filament formation in vitro David J. Townsend , Barbora Mala , Eleri Hughes , Rohanah Hussain , Giuliano Siligardi , Nigel J. Fullwood , David A. Middleton Acs Chemical Neuroscience DOI: 10.1021/acschemneuro.0c00154 Diamond Proposal Number(s): [17645, 24138] Show Abstract ▼ Abstract: Potential drug treatments for Alzheimer’s disease (AD) may be found by identifying compounds that block the assembly of the microtubule-associated protein tau into neurofibrillar tangles associated with neuron destabilisation and cell death. Here, a small library of structurally diverse compounds was screened in vitro for the ability to inhibit tau aggregation, using high-throughput synchrotron radiation circular dichroism (HT-SRCD) as a novel tool to monitor the structural changes in the protein as it assembles into filaments. The catecholamine epinephrine was found to be the most effective tau aggregation inhibitor of all 88 compounds screened. Subsequently, we tested chemically-similar phenolamine drugs from the β-adrenergic receptor (βAR) agonist class, using conventional circular dichroism spectroscopy, thioflavin T fluorescence and transmission electron microscopy. Two compounds, salbutamol and dobutamine, used widely in the treatment of respiratory and cardiovascular disease, impede the aggregation of tau in vitro. Dobutamine reduces both the rate and yield of tau filament formation over 24 hours, although it has little effect on the structural transition of tau into β-sheet structures over 24 hours. Salbutamol also reduces the yield and rate of filament formation, and additionally inhibits tau’s structural change into β-sheet rich aggregates. Salbutamol has a good safety profile and a half-life that facilitates permeation through the blood brain barrier and could represent an expediated approach to developing AD therapeutics. These results provide the motivation for in vivo evaluation of pre-existing β-adrenergic receptor agonists as a potential therapy for AD through the reduction of tau deposition in AD.	Jun 2020
B23-Circular Dichroism	Ceftriaxone blocks the polymerization of α-synuclein and exerts neuroprotective effects in vitro Paolo Ruzza , Giuliano Siligardi , Rohanah Hussain , Anna Marchiani , Mehmet Islami , Luigi Bubacco , Giovanna Delogu , Davide Fabbri , Maria A. Dettori , Mario Sechi , Nicolino Pala , Ylenia Spissu , Rossana Migheli , Pier A. Serra , Gianpietro Sechi Acs Chemical Neuroscience 5 (1) DOI: 10.1021/cn400149k PMID: 24099687 Diamond Proposal Number(s): [8304] Show Abstract ▼ Abstract: The β-lactam antibiotic ceftriaxone was suggested as a therapeutic agent in several neurodegenerative disorders, either for its ability to counteract glutamate-mediated toxicity, as in cerebral ischemia, or for its ability to enhance the degradation of misfolded proteins, as in Alexander’s disease. Recently, the efficacy of ceftriaxone in neuroprotection of dopaminergic neurons in a rat model of Parkinson’s disease was documented. However, which characteristics of ceftriaxone mediate its therapeutic effects remains unclear. Since, at the molecular level, neuronal α-synuclein inclusions and pathological α-synuclein transmission play a leading role in initiation of Parkinson-like neurodegeneration, we thought of investigating, by circular dichroism spectroscopy, the capability of ceftriaxone to interact with α-synuclein. We found that ceftriaxone binds with good affinity to α-synuclein and blocks its in vitro polymerization. Considering this finding, we also documented that ceftriaxone exerts neuroprotective action in an in vitro model of Parkinson’s disease. Our data, in addition to the findings on neuroprotective activity of ceftriaxone on Parkinson-like neurodegeneration in vivo, indicates ceftriaxone as a potential agent in treatment of Parkinson’s disease.	Oct 2013

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