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3,962 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
I04-Macromolecular Crystallography	Identification of novel CLK1 inhibitors by computational fragment-based ligand design, co-crystallization, chemical synthesis and structure activity relationships Stéphane Bourg , Matthieu Place , Chloé Copin , Apirat Chaikuad , Thomas Robert , Hanna Holzmann , Susanne Müller , Stéphane Bach , Sandrine Ruchaud , Stefan Knapp , Frédéric Buron , Sylvain Routier , Pascal Bonnet European Journal Of Medicinal Chemistry 315 DOI: 10.1016/j.ejmech.2026.118977 Show Abstract ▼ Abstract: CLK1 is one of the four human isoforms of the cdc2-like (CLK) kinases that has been suggested as a therapeutic target in diverse diseases based on its important role regulating mRNA splicing. For example, CLKs and closely related kinases such as DYRK1A have been targeted in Alzheimer’s disease and other diseases in which splice site selection contributes to the disease development. Here we have developed an efficient in silico fragment-based ligand design approach to identify novel CLK1 inhibitors with excellent ligand efficiency based on an imidazo[2,1-b][1,3,4]thiadiazole fragment. More than one million docking poses were generated from 26,225 unique virtual compounds, and after applying several filtering steps, 11 compounds were selected, synthesized and their CLK1 inhibition and cellular potency were evaluated. Gratifyingly, inhibitor potencies were in excellent agreement with predicted values and crystallographic data of an inhibitor bound to CLK1 confirmed the unusual binding mode of the compounds.	Oct 2026
I04-Macromolecular Crystallography	Structural characterization of an S8 protease from Fervidobacterium pennivorans reveals a unique tyrosine-rich β-hairpin Michail W. Kruger , Gabriela C. Schröder , Rubén Javier-López , Carmien Tolmie , Ana C. Ebrecht , Jennifer A. Littlechild , Jean Armengaud , Nils-Kåre Birkeland , Diederik J. Opperman Enzyme And Microbial Technology 199 DOI: 10.1016/j.enzmictec.2026.110904 Diamond Proposal Number(s): [28402, 35088] Open Access Show Abstract ▼ Abstract: Keratin is an abundant structural fibrous protein and extremely recalcitrant biopolymer. β-Keratin is the major constituent of feathers, which, due to the widespread poultry industry, has become a major waste product. Biotechnological upcycling of feather waste has gained interest as various bacteria and fungi capable of degrading keratin have been isolated. These microorganisms produce proteases, termed keratinases, responsible for the enzymatic hydrolysis of keratin. The structural properties that confer keratinolytic activity to proteases are, however, not well understood. Here, we investigated the structure-function relationship of a subtilisin-like S8 endopeptidase (FerB) from the thermophile Fervidobacterium pennivorans strain T. FerB was crystallized and its structure solved to 1.5 Å resolution, revealing an auto-processed state where the pro-peptide domain is non-covalently attached to the catalytic domain. The carboxyl group of the scissile peptide bond is coordinated in the active site within hydrogen bonding distance of the catalytic triad’s serine residue. Unlike fervidolysin, no β-sandwich domains are present. However, a tyrosine-rich β-hairpin structure is found in the corresponding position within the FerB structure. Deletion of the β-hairpin reduced the protein’s integrity and keratinase activity.	Aug 2026
Krios I-Titan Krios I at Diamond	Enantioselective synthesis of lactic acid from CO2 using a novel pyruvate decarboxylase in a scalable biocatalytic cascade Silvia Fruncillo , Daan M. Van Vliet , Jurgen J. Mateman , Dirk C. Van Seijst , Jan Stoutjesdijk , Jason Van Rooyen , Akash Pandya , James Galman , Annette Alcasabas , Tom A. Ewing Advanced Synthesis & Catalysis 368 DOI: 10.1002/adsc.70557 Diamond Proposal Number(s): [37221] Open Access Show Abstract ▼ Abstract: Biocatalytic cascades offer a promising route for CO2-fixation into valuable chemicals, addressing the urgent need for efficient, sustainable technologies to reduce CO2 emissions. This paper describes an enzymatic route converting gaseous CO2 and acetaldehyde into enantiopure lactic acid, widely used in diverse industries. A newly characterized pyruvate decarboxylase from Neoasia chiangmaiensis (NcPDC) enabled acetaldehyde carboxylation to pyruvate. To suppress the competing carboligation to acetoin, acetaldehyde was reversibly trapped with Tris. Pyruvate was reduced to lactate by lactate dehydrogenase, coupled with glucose dehydrogenase for NADH regeneration via D-glucose oxidation to D-gluconic acid. Up to 65% lactate yield was achieved. Repeated acetaldehyde dosing resulted in a 27 mM titer, representing a >100-fold improvement over previous reports. At 0.5 L scale, using a gas mixture mimicking industrial-grade CO2, we obtained 21 mM D-(–)-lactic acid, 42% yield and >98% e.e., demonstrating scalability and robustness. Finally, replacing the D-(–)-selective lactate dehydrogenase with an L-(+)-selective variant at small scale enabled production of L-(+)-lactic acid at 41% yield and >93% e.e, allowing switchable access to either enantiomer. A volumetric productivity of 1.1 × 10−2 g L−1 h−1 ranks among the most efficient minimal enzymatic routes developed to date for CO2-to-lactate conversion.	Jun 2026
I03-Macromolecular Crystallography	Global identification of Chromobacterium violaceum T6SS effectors reveals an Rhs antibacterial toxin featuring FIX and ADP-ribosyltransferase domains Júlia A. Alves , Genady Pankov , Andrew M. Frey , Matthias Trost , Germán G. Sgro , Sarah J. Coulthurst , José F. Da Silva Neto Journal Of Biological Chemistry 197 DOI: 10.1016/j.jbc.2026.113216 Diamond Proposal Number(s): [26793] Open Access Show Abstract ▼ Abstract: Bacteria coexist in polymicrobial communities where they engage in complex interactions, including interbacterial antagonism. The environmental bacterial pathogen Chromobacterium violaceum possesses an active type VI secretion system (T6SS), which relies mainly on VgrG3 for its activity and role in interbacterial competition. However, the arsenal of toxic effectors delivered by this T6SS remains unknown. Here, we identify the repertoire of C. violaceum T6SS effectors and characterize a novel antibacterial Rhs-family effector, RhsF (Rhs with a FIX domain), and its cognate immunity protein, RhsFi. Using mass spectrometry analyses of secreted proteins and proteins co-immunoprecipitated with VgrG3, we identified six novel effector candidates, namely four phospholipases, a protein of unknown function, and the previously-uncharacterized Rhs protein, RhsF (CV_1431). RhsF contains an N-terminal FIX domain and can intoxicate susceptible bacteria in a T6SS-dependent manner. The action of the C-terminal toxin domain of RhsF (RhsF-CT) is prevented by RhsFi (CV_1430), confirming that RhsF-RhsFi comprises an effector-immunity pair. The structure of the RhsF-CT/RhsFi complex determined by X-ray crystallography (1.85 Å resolution) revealed that RhsF-CT shares structural similarity with ADP-ribosyltransferase toxins and that RhsFi inhibits toxicity via direct occlusion of the RhsF-CT catalytic site. Functional assays indicated that RhsF-CT ADP-ribosylates RNA in vitro and that RhsF toxicity requires a catalytic triad composed of R1403, Y1456, and E1497 residues. Overall, our findings reveal effectors secreted by the T6SS of C. violaceum, establish RhsF as a potent antibacterial toxin, and confirm T6SS-dependent delivery of a FIX-containing Rhs protein, expanding the known repertoire of bacterial arms involved in microbial competition.	Jun 2026
B21-High Throughput SAXS	Polyelectrolyte-like behavior, pH-dependent self-assembly, and emulsion stabilizing properties of a model surfactant-like peptide bearing pyridine groups Valeria Castelletto , Jani Seitsonen , Ian W. Hamley Biomacromolecules 41 DOI: 10.1021/acs.biomac.6c00476 Diamond Proposal Number(s): [37575, 38954, 40960] Open Access Show Abstract ▼ Abstract: A surfactant-like peptide (SLP) bearing six non-native 3-(4-pyridyl)-l-alanine (Pal) residues and a C-terminal arginine residue, Pal6R, is shown to exhibit pH-dependent self-assembly which arises from the acid–base properties of the Pal residue (pKa ∼ 5). At a native pH of 2.4, “polyelectrolyte” correlation hole scattering is observed due to the electrostatic repulsion of highly charged molecules. The scaling of the domain size with concentration agrees with theoretical predictions for weakly charged flexible polyelectrolytes in a semidilute solution. In contrast, twisted nanotapes are observed at pH 7. The nanotapes are shown to comprise β-sheet structures packed in interdigitated bilayers. Atomistic molecular dynamics (MD) simulations confirmed the bilayer structure of the nanotapes, with extensive hydrogen bonding, and a twisting tendency. The novel SLP can stabilize water-in-oil emulsions at pH 7, forming β-sheet bilayer structures at the water droplet interface. Pal6R represents a model polyelectrolyte system with additional self-assembly and emulsion stabilization properties at neutral pH.	Jun 2026
I03-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Variant-dependent pharmacological rescue of phenylalanine hydroxylase supports a precision therapeutic strategy for phenylketonuria María Conde-Giménez , Sandra Salillas , María Galiana-Cameo , Juan E. Martínez-Oliván , Alejandro Mahía , Manuel Ledesma , Juan José Galano-Frutos , Ritwik Maity , Adrián Velázquez-Campoy , María D. Díaz-De-Villegas , Ramon Hurtado-Guerrero , Javier Sancho Biomedicine & Pharmacotherapy 199 DOI: 10.1016/j.biopha.2026.119371 Diamond Proposal Number(s): [14739] Open Access Show Abstract ▼ Abstract: henylketonuria (PKU) is an inherited metabolic disorder caused by pathogenic variants in phenylalanine hydroxylase (PAH), leading to toxic phenylalanine accumulation and severe neurological complications if untreated. Current pharmacological treatment relies on tetrahydrobiopterin (BH4), which benefits only a subset of patients, highlighting a major unmet need for alternative therapies. Here, we combined high-throughput screening, computational modelling, and drug repurposing to identify pharmacological chaperones capable of rescuing PAH function. We evaluated 26 structurally diverse small molecules in HEK293T cells expressing wild-type PAH or one of eight PKU-associated variants spanning phenotypes from mild to classical disease. Chaperoning efficacy was strongly variant-dependent, and for every variant tested at least one compound produced a greater activity increase than BH4 under identical assay conditions. Notably, belinostat, a clinically approved histone deacetylase inhibitor, emerged as the most effective compound for several clinically severe variants. Mechanistically, functional rescue consistently correlated with an increased population of tetrameric, catalytically competent PAH, as quantified by mass photometry. The crystal structure of the PAH–belinostat complex (PDB ID: 9T1O), together with structural models for all compounds, provide a framework for rational optimization. These results establish a preclinical proof-of-concept for genotype-guided pharmacological chaperone therapy in PKU and support the feasibility of personalized, variant-specific treatment strategies.	Jun 2026
I03-Macromolecular Crystallography	Structure-guided optimization of novel inhibitors of Plasmodium lysyl-tRNA synthetase with multistage activity against malaria parasites Barbara Forte , Fiona Bellany , Peter S. Campbell , Giulia Chemi , Alice Dawson , Mark Anderson , Yaw Aniweh , Anna Y. Burkhard , Anna Caroline Campos Aguiar , Alisje Churchyard , Caitlin A. Cooper , Amália Dos Santos Ferreira , Mufuliat Toyin Famodimu , Francis G. Fang , Xiao Hu , Tonnie Huijs , Delphine Baud , Chimed Jansen , María Belén Jiménez Díaz , Roger Bonnert , Susan Boyd , Benigno Crespo-Fernández , Branko Mitasev , Simone Montagna , Sachel Mok , Dinakaran Murugesan , Sunil K. Narwal , Neil R. Norcross , John Okombo , Heekuk Park , Caroline Peet , Dhelio B. Pereira , John M. Post , Janette Reader , Jennifer Riley , David A. Robinson , Raku Shinkyo , Frederick R. C. Simeons , Laura Simpson , Alasdair Smith , Dennis Smith , Josefine Striepen , Carolina B. G. Teles , Rianne Van Der Laak , Anne-Catrin Uhlemann , Amélie Vantaux , Caroline Wilson , Benoît Witkowski , Gavin Wood , Tomas Yeo , Fabio Zuccotto , Iñigo Angulo-Barturen , Jake Baum , Judith M. Bolscher , Rafael Victorio Carvalho Guido , Lyn-Marié Birkholtz , Michael J. Delves , Laurent Dembele , David A. Fidock , Francisco Javier Gamo , Dennis E. Kyle , Steven P. Maher , Jean Popovici , Chris Walpole , Fabian Gusovsky , Paul A. Willis , Kevin D. Read , Ian H. Gilbert , Beatriz Baragaña Journal Of Medicinal Chemistry 45 DOI: 10.1021/acs.jmedchem.6c00823 Diamond Proposal Number(s): [10071, 26793] Open Access Show Abstract ▼ Abstract: A fused dihydropyrrolidino-pyrimidine hit with low lipophilicity and excellent ligand efficiency was identified in a biochemical screen of the Global Health Chemical Diversity Library (GHCDL) against Plasmodium lysyl-tRNA synthetase (KRS). Structure-guided lead optimization delivered analogues with potent parasite growth inhibition, excellent biochemical and cellular selectivity (>1000-fold), and oral efficacy in the malaria NOD-scid-IL2Rγnull (SCID) mouse model. Structural information and computational methods were deployed to identify a potent and selective basic KRS inhibitor (30) with an extended half-life to reduce the dose regimen to a single-dose cure. Compound 30 displayed a long half-life across preclinical species, favorable safety, and activity across Plasmodium species as well as against drug-resistant and sensitive P. falciparum strains and field isolates. Unfortunately, 30 lacked oral bioavailability, which could not be mitigated with a prodrug approach. Nevertheless, learnings from this series will assist future KRS programs in delivering a clinical candidate with this novel mode of action.	Jun 2026
	Substrate-selective inhibition of the SARS-CoV-2 papain-like protease: inhibition of hydrolysis of human over viral substrates Sakshi Sharma , Peter A. C. Wing , Wojtek Trede , Shyam Basak , Simeon D. Draganov , Taylah Andrews-Clark , Eidarus Salah , Petra Lukacik , Claire Strain-Damerell , Adán Pinto‐fernández , Martin A. Walsh , Fernanda Duarte , Christopher J. Schofield , Lennart Brewitz Chemistry – A European Journal 6 DOI: 10.1002/chem.71248 Open Access Show Abstract ▼ Abstract: The SARS-CoV-2 papain-like protease (PLpro) and the main protease (Mpro) catalyze hydrolysis of the viral polyproteins pp1a/1ab into functional nonstructural proteins. PLpro and Mpro are medicinal chemistry targets, with Mpro inhibitors being used for COVID-19 treatment. PLpro also catalyzes hydrolysis of ubiquitin and interferon-stimulated gene 15 (ISG15) from post-translationally modified human proteins. Here we report how screening of reported deubiquitinase inhibitors using solid-phase extraction coupled to mass spectrometry assays with oligopeptide substrates based on pp1a/1ab and on an ISG15-modified human protein enabled the identification of substrate-selective PLpro inhibitors. The results reveal that the deubiquitinase inhibitor ML364 selectively inhibits the deISGylase activity of isolated PLpro over its pp1a/1ab-processing activity. Structure-activity relationship and computational studies support the assignment of ML364 and derivatives as substrate-selective PLpro inhibitors. The combined results provide proof-of-concept for developing substrate-selective inhibitors of PLpro and, by implication, related proteolytic enzymes, including deubiquitinases.	Jun 2026
Krios I-Titan Krios I at Diamond	Design principles of a membrane-spanning ubiquitin ligase Carys Williams , Laura M. Nocka , George Hedger , Pragya Parashara , Els Pardon , Naomi R. Latorraca , Ganesh V. Pusapati , Parijat Sarkar , Dorothy Lartey , Lei Gao , Ljiljana Milenkovic , Rod Chalk , Jan Steyaert , Susan Marqusee , Loic Carrique , J. Fernando Bazan , Sarah L. Rouse , Jennifer H. Kong , Christian Siebold , Rajat Rohatgi Molecular Cell 86, 2207 - 2222.e16 DOI: 10.1016/j.molcel.2026.05.001 Diamond Proposal Number(s): [28713] Open Access Show Abstract ▼ Abstract: Receptor-type E3 ubiquitin ligases enable extracellular signals to control ubiquitylation in the cytoplasm, playing widespread roles in development, metabolism, and immunity. Using cryoelectron microscopy, integrated with biophysical and functional studies, we visualized a human E3 complex composed of two transmembrane proteins, MEGF8 and MOSMO, and the intracellular RING-family protein MGRN1. This MEGF8-MOSMO-MGRN1 (MMM) complex attenuates Hedgehog signaling by ubiquitylating Smoothened (SMO), a G-protein-coupled receptor (GPCR) that transduces morphogen signals. A long helix in the MMM complex engages SMO using an intramembrane degron and extends into the cytoplasm to suspend an activated and precisely oriented RING domain below the plasma membrane. This architecture enables ubiquitylation of the cytoplasmic surface of SMO, reducing SMO abundance at primary cilia. Our structure provides insights into MEGF8 mutations, which cause multi-organ birth defects, and defines a paradigm for how transmembrane E3 ligases control the cell surface abundance of GPCRs and other signaling receptors.	Jun 2026
I03-Macromolecular Crystallography	Synthesis of novel serine β-lactamase inhibitors Justin Young Ho Show Abstract ▼ Abstract: The widespread emergence of bacterial resistance to β-lactam antibiotics, driven primarily by serine β-lactamases (SBLs), continues to threaten the clinical utility of this cornerstone class of antibacterial agents. Although β-lactamase inhibitors such as sulbactam and tazobactam have historically restored the activity of partner antibiotics, their effectiveness has been eroded by the proliferation of inhibitor-resistant enzymes, particularly class C (AmpC) and class D (OXA) β-lactamases. Consequently, there remains a pressing need for new inhibitor scaffolds that combine potent enzyme inhibition with improved chemical stability and tunable physicochemical properties. This thesis explores sulfoximine substitution on the penam scaffold as a strategy to expand the chemical and biological properties of β-lactamase inhibitors. Sulfoximines offer distinct advantages over classical sulfones, including stereochemical control, dual hydrogen-bond donor/acceptor capability, and enhanced opportunities for structural diversification. Leveraging recent advances in nitrene-transfer chemistry, robust and stereocontrolled synthetic routes to penam-sulfoximines were developed from sulbactam-derived sulfoxides. Both (S)- and (R)-configured penam sulfoximines were prepared, including synthetically challenging NH-sulfoximines that closely mimic the parent sulbactam framework. Single-crystal X-ray diffraction confirmed stereochemical integrity and structural assignments. The scope and limitations of sulfoximine N-functionalization were systematically investigated, enabling access to amide, urea, and N-aryl derivatives while revealing intrinsic stability constraints of the penam core under basic or reductive conditions. These studies establish a versatile synthetic platform for the generation of structurally diverse penam-sulfoximines suitable for biological evaluation. Biochemical and microbiological studies demonstrated that penam-sulfoximines are potent inhibitors of clinically relevant SBLs, including AmpC and OXA-type enzymes. A free NH penam-sulfoximine displayed particularly strong enzyme inhibition and measurable antibacterial activity against Acinetobacter baumannii, supported by enzyme inhibition assays, protein-binding studies, antimicrobial susceptibility testing, and structural characterization of enzyme–inhibitor complexes. However, many substituted sulfoximines exhibited reduced stability under physiological conditions, highlighting a trade-off between potency and chemical robustness. Overall, this work establishes penam-sulfoximines as a chemically accessible and biologically active class of β-lactamase inhibitors, delineates key structure–stability–activity relationships, and provides a foundation for the future design of sulfoximine-based agents targeting resistant Gram-negative pathogens.	Jun 2026

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