The reported high-yield synthesis of Medin, the most common human amyloid, uses automated solid-phase peptide synthesis (SPPS) with pseudoproline dipeptides and a removable aggregation-suppressing linker. After linker removal, synthetic Medin exhibits identical ThT kinetics and amyloid fibrils as natural Medin. This method enables high-purity production of Medin and analogs, aiding research into its role in Alzheimer’s disease. (Figure created in BioRender.com) (Institute and/or researcher Twitter usernames: https://x.com/VIB_Switch_Lab
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ABSTRACT
Medin, a 50-amino acid fragment derived from the protein MFG-E8 (lactadherin), is the most prevalent amyloid found in humans, present in the vasculature of nearly all individuals over the age of 50. Its biological relevance is highlighted by its co-localization with amyloid-β (Aβ) deposits in both Alzheimer’s disease patients and transgenic mice models. Notably, Medin promotes amyloid-β aggregation, forming mixed fibrils with Aβ and enhancing its deposition in blood vessels. Here we report a new and efficient strategy to chemically access this compound. Our approach employs a solubilizing linker that not only ensures high solubility but also suppresses aggregation, allowing efficient purification of the product. The linker can be removed without a trace, after which the product behaves identically to wild-type Medin and forms amyloid fibrils. The synthesis route allows opening up a new chemical space, including nonnatural modifications like biotinylation. Together with the control over the aggregation properties, this is a powerful tool for amyloid protein studies.
