Identification of a nanomolar affinity α-synuclein fibril imaging probe by ultra-high throughput <i>in silico</i> screening

Ferrie, John J.; Lengyel‐Zhand, Zsofia; Janssen, Bieneke; Lougee, Marshall G.; Giannakoulias, Sam; Hsieh, Chia-Ju; Pagar, Vinayak Vishnu; Weng, Chi Chang; Xu, Hong; Graham, Thomas J. A.; Lee, Virginia M.‐Y.; Mach, Robert H.; Petersson, E. James

doi:10.1039/d0sc02159h

Cited by 37 publications

(52 citation statements)

References 46 publications

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“…In vitro ARG was performed using brain tissue from A53T PD mice (15 months old). Images confirmed binding of [ 125 I]83 to α-syn rich brain regions [ 139 ]. Further efforts are needed to decrease unspecific protein binding and increase selectivity.…”

Section: Alpha-synuclein Pet Tracer Development—from a Molecular Development Point Of Viewmentioning

confidence: 85%

“…Since para substituents and in particular fluoro substituents show decreased binding, while moderate to strong binding is demonstrated by derivatives bearing electron donating groups such as methyl and methoxy groups. As a general trend, non-planar compounds showed weaker binding than the planar compounds exemplified in Figure 26 D ( 80 and 81 ) [ 121 , 139 ]. Similar observations were previously drawn for other structural classes.…”

Section: Alpha-synuclein Pet Tracer Development—from a Molecular Development Point Of Viewmentioning

confidence: 99%

“…( B ) Chemical structure of compounds 66 , 67 and general structure of most potent α-syn binders. Table represents IC 50 values screened for BS2 and BS9 using [ 3 H]Tg-190b and [ 3 H]BF2846 [ 139 ]. * clogP values were calculated by BioByte.…”

Section: Figurementioning

confidence: 99%

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Alpha-Synuclein PET Tracer Development—An Overview about Current Efforts

et al. 2021

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Neurodegenerative diseases such as Parkinson’s disease (PD) are manifested by inclusion bodies of alpha-synuclein (α-syn) also called α-synucleinopathies. Detection of these inclusions is thus far only possible by histological examination of postmortem brain tissue. The possibility of non-invasively detecting α-syn will therefore provide valuable insights into the disease progression of α-synucleinopathies. In particular, α-syn imaging can quantify changes in monomeric, oligomeric, and fibrillic α-syn over time and improve early diagnosis of various α-synucleinopathies or monitor treatment progress. Positron emission tomography (PET) is a non-invasive in vivo imaging technique that can quantify target expression and drug occupancies when a suitable tracer exists. As such, novel α-syn PET tracers are highly sought after. The development of an α-syn PET tracer faces several challenges. For example, the low abundance of α-syn within the brain necessitates the development of a high-affinity ligand. Moreover, α-syn depositions are, in contrast to amyloid proteins, predominantly localized intracellularly, limiting their accessibility. Furthermore, another challenge is the ligand selectivity over structurally similar amyloids such as amyloid-beta or tau, which are often co-localized with α-syn pathology. The lack of a defined crystal structure of α-syn has also hindered rational drug and tracer design efforts. Our objective for this review is to provide a comprehensive overview of current efforts in the development of selective α-syn PET tracers.

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Section: Alpha-synuclein Pet Tracer Development—from a Molecular Development Point Of Viewmentioning

confidence: 85%

Section: Alpha-synuclein Pet Tracer Development—from a Molecular Development Point Of Viewmentioning

confidence: 99%

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Alpha-Synuclein PET Tracer Development—An Overview about Current Efforts

et al. 2021

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“…These structures have enabled the development of structure-based drug discovery approaches, including in particular the identification of peptide-based inhibitors to prevent a-synuclein aggregation (15,16). Furthermore, binding sites along the surface of a-synuclein fibrils for the development of diagnostics tools have also been identified (17)(18)(19)(20). These developments are relevant considering the current lack of radiotracers for measuring the accumulation of asynuclein aggregates in the human brain, and that such diagnostics tools may eventually enable the presymptomatic diagnosis of synucleinopathies (17,(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies have used high-throughput docking approaches to identifying asynuclein fibril-binding compounds (17)(18)(19)(20). However, because of the great technical difficulties in establishing reproducible high-throughput kinetic assays to monitor asynuclein aggregation, the experimental validation of the compounds predicted from computational screenings has been challenging.…”

Section: Introductionmentioning

confidence: 99%

Structure-based discovery of small molecule inhibitors of the autocatalytic proliferation of α-synuclein aggregates

Chia

Brotzakis

Horne

et al. 2021

Preprint

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The presence of amyloid fibrils of α-synuclein is closely associated with Parkinson’s disease and related synucleinopathies. It is still very challenging, however, to systematically discover small molecules that prevent the formation of these aberrant aggregates. Here, we describe a structure-based approach to identify small molecules that specifically inhibit the surface-catalyzed secondary nucleation step in the aggregation of α-synuclein by binding to the surface of the amyloid fibrils. The resulting small molecules are screened using a combination of kinetic and thermodynamic assays for their ability to bind α-synuclein fibrils and prevent the further generation of toxic oligomers. This study demonstrates that the combination of structure-based and kinetic-based drug discovery methods can lead to the identification of small molecules that selectively inhibit the autocatalytic proliferation of α-synuclein aggregates.

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PET Ligands for Imaging Mutant Huntingtin Aggregates: A Case Study in Non‐For‐Profit Scientific Management

Dickmann,

Milicevic Sephton,

Barker

et al. 2024

ChemBioChem

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Positron emission tomography imaging of misfolded proteins with high‐affinity and selective radioligands has played a vital role in expanding our knowledge of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. The pathogenesis of Huntington's disease, a CAG trinucleotide repeat disorder, is similarly linked to the presence of protein fibrils formed from mutant huntingtin (mHTT) protein. Development of mHTT fibril–specific radioligands has been limited by the lack of structural knowledge around mHTT and a dearth of available hit compounds for medicinal chemistry refinement. Over the past decade, the Cure Huntington's Disease Initiative (CHDI), a non‐for‐profit scientific management organisation has orchestrated a large‐scale screen of small molecules to identify high affinity ligands of mHTT, with lead compounds now reaching clinical maturity. Here we describe the mHTT radioligands developed to date and opportunities for further improvement of this radiotracer class.

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Identification of a nanomolar affinity α-synuclein fibril imaging probe by ultra-high throughput in silico screening

Abstract: Ultra-high throughput in silico screening identified molecules that bind to α-synuclein fibrils, which were analyzed by photo-crosslinking, structure-activity studies, and radioligand binding to validate this approach for finding imaging probes.

Cited by 37 publications

References 46 publications

Alpha-Synuclein PET Tracer Development—An Overview about Current Efforts

Alpha-Synuclein PET Tracer Development—An Overview about Current Efforts

Structure-based discovery of small molecule inhibitors of the autocatalytic proliferation of α-synuclein aggregates

PET Ligands for Imaging Mutant Huntingtin Aggregates: A Case Study in Non‐For‐Profit Scientific Management

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