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Misfolding and aggregation of amyloid peptides are critical pathological events in numerous protein misfolding diseases (PMDs), such as Alzheimer's disease (AD), type II diabetes (T2D), and medullary thyroid carcinoma (MTC). While developing effective amyloid detectors and inhibitors to probe and prevent amyloid aggregation is a crucial diagnostic and therapeutic strategy for treating debilitating diseases, it is important to recognize that amyloid detection and amyloid prevention are two distinct strategies for developing pharmaceutical drugs. Here, we reported novel fluorescent BO21 as a versatile “dual-function, multi-target” amyloid probe and inhibitor for detecting and preventing amyloid aggregates of different sequences (Aβ, hIAPP, or hCT) and sizes (monomers, oligomers, or fibrils). As an amyloid probe, BO21 demonstrated a higher sensitivity and binding affinity to oligomeric and fibrillar amyloids compared to ThT, resulting in up to 18–39 fold fluorescence enhancements. As an amyloid inhibitor, BO21 also demonstrated its strong amyloid inhibition property by effectively preventing amyloid aggregation, disaggregating preformed amyloid fibrils, and reducing amyloid-induced cytotoxicity. The findings of this study offer a new perspective for the discovery of dual-functional amyloid probes and inhibitors, which have the potential to greatly expand the diagnostic and therapeutic treatments available for PMDs.
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Big versus small: The impact of aggregate size in disease
Abstract Protein aggregation results in an array of different size soluble oligomers and larger insoluble fibrils. Insoluble fibrils were originally thought to cause neuronal cell deaths in neurodegenerative diseases due to their prevalence in tissue samples and disease models. Despite recent studies demonstrating the toxicity associated with soluble oligomers, many therapeutic strategies still focus on fibrils or consider all types of aggregates as one group. Oligomers and fibrils require different modeling and therapeutic strategies, targeting the toxic species is crucial for successful study and therapeutic development. Here, we review the role of different‐size aggregates in disease, and how factors contributing to aggregation (mutations, metals, post‐translational modifications, and lipid interactions) may promote oligomers opposed to fibrils. We review two different computational modeling strategies (molecular dynamics and kinetic modeling) and how they are used to model both oligomers and fibrils. Finally, we outline the current therapeutic strategies targeting aggregating proteins and their strengths and weaknesses for targeting oligomers versus fibrils. Altogether, we aim to highlight the importance of distinguishing the difference between oligomers and fibrils and determining which species is toxic when modeling and creating therapeutics for protein aggregation in disease.
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- Award ID(s):
- 2210963
- PAR ID:
- 10423119
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Protein Science
- Volume:
- 32
- Issue:
- 7
- ISSN:
- 0961-8368
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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