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Exploring IDP-Ligand Interactions: tau K18 as A Test Case.

ABSTRACT: Over the past decade intrinsically disordered proteins (IDPs) have emerged as a biologically important class of proteins, many of which are of therapeutic relevance. Here, we investigated the interactions between a model IDP system, tau K18, and nine literature compounds that have been reported as having an effect on tau in order to identify a robust IDP-ligand system for the optimization of a range of biophysical methods. We used NMR, surface plasmon resonance (SPR) and microscale thermophoresis (MST) methods to investigate the binding of these compounds to tau K18; only one showed unambiguous interaction with tau K18. Several near neighbors of this compound were synthesized and their interactions with tau K18 characterized using additional NMR methods, including 1D ligand-observed NMR, diffusion-ordered spectroscopy (DOSY) and 19F NMR. This study demonstrates that it is possible to detect and characterize IDP-ligand interactions using biophysical methods. However, care must be taken to account for possible artefacts, particularly the impact of compound solubility and where the protein has to be immobilized.

SUBMITTER: Vagrys D

PROVIDER: S-EPMC7432903 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Exploring IDP-Ligand Interactions: tau K18 as A Test Case.

Vagrys Darius D Davidson James J Chen Ijen I Hubbard Roderick E RE Davis Ben B

International journal of molecular sciences 20200724 15

Over the past decade intrinsically disordered proteins (IDPs) have emerged as a biologically important class of proteins, many of which are of therapeutic relevance. Here, we investigated the interactions between a model IDP system, tau K18, and nine literature compounds that have been reported as having an effect on tau in order to identify a robust IDP-ligand system for the optimization of a range of biophysical methods. We used NMR, surface plasmon resonance (SPR) and microscale thermophoresi ...[more]

PMID: 32722166

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Project description:Imaging of pathological tau with positron emission tomography (PET) has the potential to allow early diagnosis of the dementias and monitoring of disease progression, including assessment of therapeutic interventions, in vivo. The first generation of tau PET tracers, including the carbazole flortaucipir and the 2-arylquinolines of the THK series, are now used in clinical research; however, concerns have been raised about off-target binding and low sensitivity.With the aim to determine the nature of tau pathology depicted by structurally distinct tau ligands we carried out a microscopic neuropathological evaluation in post-mortem human brain tissue of cases with primary and secondary tauopathies. Carbazole and 2-arylquinoline binding was only observed in cases with Alzheimer's disease and one case with frontotemporal dementia and parkinsonism linked to chromosome 17 exhibiting a R406W MAPT mutation. In end stage Alzheimer's disease cases, fluorescent imaging with the carbazole T726 and the 2-arylquinoline THK-5117 revealed high inter- and intra-case variability of tracer binding, and this was corroborated by quantitative phosphorimaging with the PET tracer [18F]THK-5117. Microscopic analysis of the pathological inclusions revealed that the fluorescent tracers preferentially bind to premature tau aggregates. Whilst T726 binding was limited to neuronal tau, THK-5117 additionally depicted neuritic tau. Neither tracer depicted tau in pre-symptomatic disease.Our results highlight limitations of the first generation of tau PET tracers, in particular lack of correlation between pathological tau load and tracer binding, limited sensitivity to tau in early disease, and high variability in tracer binding between and within cases. Concerns remain that these limitations may also affect the next generation tracers as they target the same high affinity binding site. Therefore, it is crucial to assess inter- and intra-subject correlation of tracer binding with pathological tau load in post-mortem tissue studies, and to rigorously assess novel tau PET tracers before translation into clinical studies.

Dataset Information

Exploring IDP-Ligand Interactions: tau K18 as A Test Case.

Publications

Exploring IDP-Ligand Interactions: tau K18 as A Test Case.

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