Docking for molecules that bind in a symmetric stack with SymDOCK DOI Creative Commons

Matthew S. Smith,

Ian Knight,

Rian C Kormos

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 29, 2023

Discovering ligands for amyloid fibrils, such as those formed by the tau protein, is an area of much current interest. In recent structures, bind in stacks fibrils to reflect rotational and translational symmetry fibril itself; these structures make few interactions with protein but interact extensively each other. To exploit this stacking, we developed SymDOCK, a method dock molecules that follow protein's symmetry. For prospective ligand pose, apply operation generate self-interacting fibril-interacting stack, checking doing so will not cause clash between original molecule its image. Absent clash, retain pose add ligand-ligand van der Waals energy ligand's docking score (here using DOCK3.8). We can check geometries energies implementation ANI, neural network-based quantum-mechanical evaluation stacking energies. retrospective calculations, reproduce poses three PET tracers whose have been determined. More convincingly,

Language: Английский

Current Progress and Future Directions in Non-Alzheimer’s Disease Tau PET Tracers DOI
Hendris Wongso, Ryuichi Harada, Shozo Furumoto

et al.

ACS Chemical Neuroscience, Journal Year: 2025, Volume and Issue: 16(2), P. 111 - 127

Published: Jan. 6, 2025

Alzheimer's disease (AD) and non-AD tauopathies are dominant public health issues driven by several factors, especially in the aging population. The discovery of first-generation radiotracers, including [18F]FDDNP, [11C]PBB3, [18F]flortaucipir, [18F]THK series, for vivo detection has marked a significant breakthrough fields neuroscience radiopharmaceuticals, creating robust new category labeled compounds: tau positron emission tomography (PET) tracers. Subsequently, other PET tracers with improved binding properties have been developed using various chemical scaffolds to target three-repeat/four-repeat (3R/4R) folds AD. In 2020, [18F]flortaucipir was approved U.S. Food Drug Administration imaging pathology adult patients cognitive deficits undergoing evaluation Despite remarkable progress development AD tracers, agents rare (4R [predominantly expressing 4R isoform], involved progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, globular glial tauopathy, 3R such as Pick's disease) remain substantially underdeveloped. this review, we discuss recent tracer development, particular emphasis on clinically validated their potential use tauopathies. Additionally, highlight critical need further specifically designed tauopathies, an area that remains significantly underexplored despite its importance advancing understanding diagnosis these disorders.

Language: Английский

Citations

2
Local structural preferences in shaping tau amyloid polymorphism DOI Creative Commons
Nikolaos Louros, Martin Wilkinson,

Grigoria Tsaka

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 3, 2024

Tauopathies encompass a group of neurodegenerative disorders characterised by diverse tau amyloid fibril structures. The persistence polymorphism across tauopathies suggests that distinct pathological conditions dictate the adopted polymorph for each disease. However, extent to which intrinsic structural tendencies cores contribute remains uncertain. Using combination experimental approaches, we here identify new amyloidogenic motif, PAM4 (Polymorphic Amyloid Motif Repeat 4), as significant contributor polymorphism. Calculation per-residue contributions stability different pathologic structures plays central role in preserving integrity polymorphs. Consistent with this, cryo-EM analysis fibrils formed from synthetic peptide shows sequence adopts alternative closely correspond disease-associated strains. Furthermore, in-cell experiments revealed deletion hampers cellular seeding efficiency aggregates extracted Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy patients, underscoring PAM4's pivotal these tauopathies. Together, our results highlight importance propensity core segments determine structure cells, propagating

Language: Английский

Citations

10
Docking for Molecules That Bind in a Symmetric Stack with SymDOCK DOI Creative Commons

Matthew S. Smith,

Ian Knight,

Rian Kormos

et al.

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(2), P. 425 - 434

Published: Jan. 8, 2024

Discovering ligands for amyloid fibrils, such as those formed by the tau protein, is an area of great current interest. In recent structures, bind in stacks fibrils to reflect rotational and translational symmetry fibril itself; these make few interactions with protein but interact extensively each other. To exploit this stacking, we developed SymDOCK, a method dock molecules that follow protein's symmetry. For prospective ligand pose, apply operation generate self-interacting fibril-interacting stack, checking doing so will not cause clash between original molecule its image. Absent clash, retain pose add ligand-ligand van der Waals energy ligand's docking score (here using DOCK3.8). We can check geometries energies implementation ANI, neural-network-based quantum-mechanical evaluation stacking energies. retrospective calculations, reproduce poses three PET tracers whose structures have been determined. More convincingly,

Language: Английский

Citations

5
Essential tremor with tau pathology features seeds indistinguishable in conformation from Alzheimer’s disease and primary age-related tauopathy DOI Creative Commons
Nil Saez-Calveras, Jaime Vaquer-Alicea, Charles L. White

et al.

Acta Neuropathologica, Journal Year: 2025, Volume and Issue: 149(1)

Published: Jan. 8, 2025

Neurodegenerative tauopathies are characterized by the deposition of distinct fibrillar tau assemblies, whose rigid core structures correlate with defined neuropathological phenotypes. Essential tremor (ET) is a progressive neurological disorder that, in some cases, associated cognitive impairment and accumulation. In this study, we explored assembly conformation ET patients pathology using cytometry-based biosensor assays. These assays quantify seeding activity present brain homogenates detecting conversion intracellular tau-fluorescent protein fusions from soluble to an aggregated state. Pathogenic assemblies exhibit barriers, where specific structure cannot serve as template for native monomer if amino acid sequences incompatible. We recently leveraged species barrier define systematically substituting alanine (Ala) into measuring its incorporation seeded aggregates within cells. This Ala scan precisely classified seeds various tauopathies. analyzed 18 patient brains pathology, robust 9 (50%) predominantly localized temporal pole cortex. further examined 8 these cases found that requirements were identical those Alzheimer's disease (AD) primary age-related tauopathy (PART), other tauopathies, such corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), supranuclear palsy (PSP). findings indicate pathologically confined subset significant cores seen AD PART. could facilitate more precise diagnosis targeted therapies presenting impairment.

Language: Английский

Citations

0
A Cooperative Model for Symmetric Ligand Binding to Protein Fibrils DOI Creative Commons

Matthew S. Smith,

William F. DeGrado, Michael Grabe

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 30, 2025

A hallmark of neurodegenerative diseases like Alzheimer's Disease (AD) and chronic traumatic encephalopathy (CTE) is the presence toxic protein aggregates in neurons. In AD CTE specifically, tau forms insoluble fibrils that are hundreds nanometers length. Intriguingly, recent experimental structures suggest ligands disaggregator EGCG positron emission tomography (PET) tracers GTP-1 MK-6240 bind to long stacks reflecting symmetry across many binding sites. these stacks, each ligand makes more contact with its mates than it does protein. To interpret molecules new ligands, we must understand effects cooperativity between sites entropy coming from number Here, investigate a nearest-neighbors model use statistical mechanics derive isotherms for saturation competition experiments. This allows us relate measured EC 50 so IC values intrinsic affinity single site ways resembling Cheng-Prusoff Equation. Depending on degree molecular species, this permits solutions lack steep curves expected cooperative systems even 2-site systems. We finally consider conditions fibril's detection PET scan practical matters fitting model's parameters data.

Language: Английский

Citations

0
How is the Amyloid Fold Built? Polymorphism and the Microscopic Mechanisms of Fibril Assembly DOI Creative Commons
Liam D. Aubrey, Sheena E. Radford

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169008 - 169008

Published: Feb. 1, 2025

Language: Английский

Citations

0
In Situ Labeling of Pathogenic Tau Using Photo-Affinity Chemical Probes DOI

Pengju Nie,

You Wu, John Robinson

et al.

ACS Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

Tau aggregation plays a crucial role in the development of Alzheimer's disease (AD). Developing specific techniques that can isolate pathogenic tau from brain tissue is important for understanding tauopathies and advancing targeted therapies. Here, we develop photoaffinity small molecular probes novel method situ labeling investigate their activity interacting with cells AD patient brains. Based on reported chemical structures PET tracers, designed synthesized two tau-specific probes, namely, Tau-2 Tau-4. After validation cell, mouse model, samples, our photolabeling results suggested effectively labels soluble cell models, while Tau-4 selectively binds high-molecular-weight aggregates late-stage tissues. Proteomic analysis verified isolation samples. Collectively, these findings underscore potential as powerful tools investigating proteins neurofibrillary tangles neurodegenerative diseases.

Language: Английский

Citations

0
Selective imaging probes for differential detection of pathological tau polymorphs in tauopathies DOI Creative Commons
Nicolò Bisi, Luca Pinzi, Giulio Rastelli

et al.

Drug Discovery Today, Journal Year: 2025, Volume and Issue: unknown, P. 104352 - 104352

Published: April 1, 2025

Tauopathies, including Alzheimer's disease (AD), Pick's (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), are characterized by the misfolding pathological aggregation of tau protein, leading to neurodegeneration. Although pathogenesis these diseases is still a matter for debate, formation amyloid inclusions represents only histopathological hallmark available. Tau not same in terms structure morphology, different tauopathies polymorphs. Remarkably, selective detection polymorphs crucial differential diagnosis, monitoring evaluation potential harmfulness polymorphs, with significant impact on drug discovery. This review discusses recent advances development imaging probes designed forms associated specific tauopathies. We explore application compounds that can target characteristic AD, PiD, PSP CBD. In particular, we focus discussing probes' selectivity sensitivity distinguishing between tauopathy-associated preclinical settings. The progress weaknesses this field discussed, guide researchers identifying accurate potent diagnosis neurodegenerative diseases.

Language: Английский

Citations

0
The Current Role of Tau PET Imaging in Neurodegeneration DOI
Greet Vanderlinden, Rik Vandenberghe, Mathieu Vandenbulcke

et al.

Seminars in Nuclear Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

Citations

0
Emerging Trends in Cryo-EM-based Structural Studies of Neuropathological Amyloids DOI
Suman Mishra

Journal of Molecular Biology, Journal Year: 2023, Volume and Issue: 435(24), P. 168361 - 168361

Published: Nov. 8, 2023

Language: Английский

Citations

8