A potential drug target for Alzheimer's disease may be more tractable now that scientists in Germany have discovered how to tether compounds that block a crucial enzyme to the cellular compartment in which the enzyme does its deadly work.
This enzyme, β-secretase, cleaves the protein APP (labelled green, left panel) to make amyloid-β peptide, which causes the plaques that contribute to neurodegeneration, in a compartment called the endosome. But soluble inhibitors do not reach this area when tested in cell cultures.
Kai Simons from the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden and his colleagues chemically modified one inhibitor by linking it to a fat-soluble sterol group. The resulting compound could anchor itself inside an endosome and efficiently block amyloid-β generation there (pictured, right panel). It also stopped the development of plaques when injected into a mouse model of Alzheimer's disease.
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Cell biology: Casting anchor. Nature 453, 4 (2008). https://doi.org/10.1038/453004a
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DOI: https://doi.org/10.1038/453004a
